Implantable polymer depots for the controlled release of therapeutic agents

ABSTRACT

The present technology relates to depot assemblies for the controlled, sustained release of a therapeutic agent. The assembly can include a depot having a therapeutic region comprising a therapeutic agent, and a control region comprising a bioresorbable polymer and a releasing agent mixed with the polymer. The releasing agent may be configured to dissolve when the depot is placed in vivo to form diffusion openings in the control region. The depot may be configured to be implanted at a treatment site in vivo and, while implanted, release the therapeutic agent at the treatment site for no less than 3 days.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of priority to PCTApplication No. PCT/US19/12795, filed Jan. 8, 2019, PCT Application No.PCT/US18/54777, filed Oct. 6, 2018, U.S. Patent Application No.62/742,357, filed Oct. 6, 2018, U.S. Patent Application No. 62/723,478,filed Aug. 28, 2018, U.S. Patent Application No. 62/670,721, filed May12, 2018, each of which is incorporated by reference herein in itsentirety.

The present application incorporates by reference each of the followingapplications in its entirety: U.S. Patent Application No. 62/569,349,filed Oct. 6, 2017, U.S. Patent Application No. 62/614,884, filed Jan.8, 2018, and U.S. Patent Application No. 62/640,571, filed Mar. 8, 2018.

TECHNICAL FIELD

The present technology relates to implants for controlled, sustainedrelease of therapeutic agents in vivo.

BACKGROUND OF THE INVENTION

Implantable systems for the controlled release of therapeutic agentsoffer advantages over other drug delivery methods, such as oral orparenteral methods. Devices comprised of biocompatible and/orbiodegradable polymers and therapeutic agents can be implanted inclinically desirable anatomic locations, thereby providing localizeddelivery of select agents. This localized delivery enables a substantialproportion of the agent to reach the intended target and undesirablesystemic side effects can be avoided. However, these systems oftensuffer from a lack of a true controlled release mechanism in that theytypically provide a burst release of drug upon contact with surroundingphysiologic fluids followed by a residual release of drug.

In order to improve drug release in certain polymer carriers,hydrophilic polymers, such as polysorbate, have been added to thesecarriers as wetting agents to accelerate or to enhance drug release frombiocompatible polymers such polyethylene glycol (PEG) in oralformulations (Akbari, J., et al., ADV. PHARM. BULL., 2015, 5(3):435-441). However, these formulations are intended to provide animmediate release of a hydrophobic drug into a hydrophilic environment(the in vivo physiologic fluid), where a substantial portion of theentire drug payload is immediately or aggressively released, not avariable or sustained controlled release.

While these drug release kinetics may be desirable in some clinicalapplications, a controlled, sustained release of a therapeutic agent canbe of clinical benefit in certain circumstances. In particular, it maybe desirable to implant a biodegradable carrier holding a large dose ofa therapeutic agent for a controlled, sustained release over time. Thismay have particular value when the carrier loaded with therapeutic agentis implanted in conjunction with an interventional or surgical procedureand, optionally, alongside or as part of an implantable medical device.

Thus, a need exists for biocompatible implantable systems capable ofproviding a highly controlled release of drug.

SUMMARY

The present technology relates to implants for controlled release of atherapeutic agent to treat a medical condition and associated systemsand methods. In particular, the present technology relates to implantsfor local, sustained release of a therapeutic agent at a surgical orinterventional site and associated systems and methods.

The subject technology is illustrated, for example, according to variousaspects described below, including with reference to FIGS. 1-65. Variousexamples of aspects of the subject technology are described as numberedclauses (1, 2, 3, etc.) for convenience. These are provided as examplesand do not limit the subject technology.

1. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region; and    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 7 days.

2. The depot of clause 1, wherein the analgesic in the therapeuticregion comprises at least 50% of the total weight of the depot.

3. The depot of clause 1 or clause 2, wherein the depot is configured torelease the analgesic at the treatment site for no less than 14 days.

4. The depot of clause 3, wherein about 20% to about 50% of theanalgesic is released in the first about 3 to about 5 days of the 14days, and wherein at least 80% of the remaining analgesic is released inthe last 11 days of the 14 days.

5. The depot of clause 3, wherein about 20% to about 40% of theanalgesic is released in the first 3 days of the 14 days, and wherein atleast 80% of the remaining analgesic is released in the last 11 days ofthe 14 days.

6. The depot of any one of clauses 3 to 5, wherein at least 90% of theremaining analgesic is released in the last 11 days of the 14 days.

7. The depot of any one of clauses 3 to 6, wherein no more than 15% ofthe amount of analgesic is released in the first 2 days of the 14 days.

8. The depot of any one of clauses 3 to 7, wherein no more than 20% ofthe amount of analgesic is released in the first 2 days of the 14 days.

9. The depot of any one of clauses 3 to 8, wherein no more than 25% ofthe amount of analgesic is released in the first 3 days of the 14 days.

10. The depot of any one of clauses 3 to 9, wherein no more than 30% ofthe amount of analgesic is released in the first 3 days of the 14 days.

11. The depot of any one of the preceding clauses, wherein the depot isconfigured to release the analgesic at a first rate for a first periodof time and at a second rate for a second period of time.

12. The depot of clause 11, wherein the first rate is greater than thesecond rate.

13. The depot of clause 11, wherein the first period of time is greaterthan the second period of time.

14. The depot of clause 11, wherein the first period of time is lessthan the second period of time.

15. The depot of any one of the preceding clauses, wherein the depot isconfigured to release at least 90% of the analgesic in the therapeuticregion within 14 days.

16. The depot of any one of the preceding clauses, wherein the depot isconfigured to release about 100 mg to about 500 mg of analgesic to thetreatment site per day.

17. The depot of any one of the preceding clauses, wherein the depot isconfigured to release about 100 mg to about 400 mg of analgesic to thetreatment site per day.

18. The depot of any one of the preceding clauses, wherein the depot isconfigured to release about 100 mg to about 300 mg of analgesic to thetreatment site per day.

19. The depot of any one of the preceding clauses, wherein the depot isconfigured to release no more than 300 mg of analgesic per day withinthe first 3 days, and no more than 200 mg per day in the remaining days.

20. The depot of any one of the preceding clauses, wherein the depot isconfigured to release no more than 150 mg of analgesic per day withinthe first 3 days, and no more than 100 mg per day in the remaining days.

21. The depot of any one of the preceding clauses, wherein no more than400 mg of analgesic is released within any day of the 14 days.

22. The depot of any one of the preceding clauses, wherein no more than300 mg of analgesic is released within any day of the 14 days.

23. The depot of any one of the preceding clauses, wherein no more than250 mg of analgesic is released within any day of the 14 days.

24. The depot of any one of the preceding clauses, wherein no more than200 mg of analgesic is released within any day of the 14 days.

25. The depot of any one of the preceding clauses, wherein no more than150 mg of analgesic is released within any day of the 14 days.

26. The depot of any one of the preceding clauses, wherein no more than100 mg of analgesic is released within any day of the 14 days.

27. The depot of any one of the preceding clauses, wherein the depot isconfigured to release the analgesic agent at the treatment site in vivofor no less than 1 day, no less than 2 days, no less than 3 days, noless than 4 days, no less than 5 days, no less than 6 days, no less than7 days, no less than 8 days, no less than 9 days, no less than 10 days,no less than 11 days, no less than 12 days, no less than 13 days, noless than 14 days, no less than 15 days, no less than 16 days, no lessthan 17 days, no less than 18 days, no less than 19 days, no less than20 days, no less than 21 days, no less than 22 days, no less than 23days, no less than 24 days, no less than 25 days, no less than 26 days,no less than 27 days, no less than 28 days, no less than 29 days, noless than 30 days, no less than 40 days, no less than 50 days, no lessthan 60 days, no less than 70 days, no less than 90 days, no less than100 days, no less than 200 days, no less than 300 days, or no less than365 days.

28. The depot of any one of the preceding clauses, wherein theconcentration of the analgesic in the blood plasma of a mammalianpatient on day 10 is no less than 70% of the concentration of theanalgesic in the blood plasma of the patient on day 5.

29. The depot of any one of the preceding clauses, wherein thetherapeutic region comprises a covered portion and an exposed portion,wherein the covered portion is covered by the control region such that,when the depot is initially positioned at the treatment site in vivo,the control region is between the covered portion of the therapeuticregion and physiologic fluids at the treatment site and the exposedportion of the therapeutic region is exposed to the physiologic fluids.

30. The depot of any one of the preceding clauses, wherein, the depothas a total surface area comprising the exposed surface area of thecontrol region plus the exposed surface area of the therapeutic region,and when the depot is initially positioned at the treatment site invivo, a ratio of the exposed surface area of the therapeutic region tothe exposed surface area of the control region is from about 5% to about20%, or from about 5% to about 15%, or from about 5% to about 10%.

31. The depot of clause 30, wherein the exposed surface area of thecontrol region is less than the exposed surface area of the therapeuticregion.

32. The depot of clause 30, wherein the exposed surface area of thecontrol region is greater than the exposed surface area of thetherapeutic region.

33. The depot of any one of the preceding clauses, wherein the controlregion is a first control region, and wherein the depot comprises asecond control region.

34. The depot of clause 33, wherein the first control region is disposedat a first side of the therapeutic region and the second control regionis disposed at a second side of the therapeutic region opposite thefirst side.

35. The depot of any one of the preceding clauses, wherein the depotcomprises a plurality of control regions and a plurality of therapeuticregions, and wherein each of the therapeutic regions is separated froman adjacent one of the therapeutic regions by one or more controlregions.

36. The depot of clause 35, wherein each of the therapeutic regions andeach of the control regions is a micro-thin layer.

37. The depot of clause 35 or clause 36, wherein the depot comprisesfrom about 2 to about 100 therapeutic regions.

38. The depot of clause 35 or clause 36, wherein the depot comprisesfrom about 2 to about 50 therapeutic regions.

39. The depot of clause 35 or clause 36, wherein the depot comprisesfrom about 2 to about 10 therapeutic regions.

40. The depot of any one of clauses 1 to 34, wherein the therapeuticregion is enclosed by the control region such that, when the depot ispositioned at the treatment site in vivo, the control region is betweenthe therapeutic region and physiologic fluids at the treatment site.

41. The depot of any one of the preceding clauses, wherein the controlregion comprises a first control layer and a second control layer.

42. The depot of clause 41, wherein the second control layer is adjacentto the therapeutic region and the first control layerencapsulates/encloses the therapeutic region and the second controllayer.

43. The depot of clause 41 or clause 42, wherein the first control layerand the second control layer together enclose the therapeutic region.

44. The depot of any one of clauses 41 to 43, wherein the first controllayer is disposed at a first side of the therapeutic region and thesecond control layer is disposed at a second side of the therapeuticregion opposite the first side.

45. The depot of any one of clauses 41 to 44, wherein the first controllayer comprises a first plurality of sub-layers and the second controllayer comprises a second plurality of sub-layers.

46. The depot of any one of clauses 41 to 45, wherein the first controllayer includes a first amount of the releasing agent and the secondcontrol layer includes a second amount of the releasing agent differentthan the first amount.

47. The depot of any one of clauses 41 to 46, wherein the second controllayer is positioned between the first control layer and the therapeuticregion, and wherein the first control layer includes a firstconcentration of the releasing agent and the second control layerincludes a second concentration of the releasing agent greater than thefirst concentration.

48. The depot of any one of clauses 41 to 46, wherein the second controllayer is positioned between the first control layer and the therapeuticregion, and wherein the first control layer includes a firstconcentration of the releasing agent and the second control layerincludes a second concentration of the releasing agent less than thefirst concentration.

49. The depot of any one of clauses 41 to 48, wherein the second controllayer is positioned between the first control layer and the therapeuticregion, and wherein

-   -   the first control layer includes up to 5% by weight of the        releasing agent, up to 10% by weight of the releasing agent, up        to 15% by weight of the releasing agent, up to 20% by weight of        the releasing agent, up to 25% by weight of the releasing agent,        up to 30% by weight of the releasing agent, up to 35% by weight        of the releasing agent, up to 40% by weight of the releasing        agent, up to 45% by weight of the releasing agent, or 50% by        weight of the releasing agent, and    -   the second control layer includes up to 5% by weight of the        releasing agent, up to 10% by weight of the releasing agent, up        to 15% by weight of the releasing agent, up to 20% by weight of        the releasing agent, up to 25% by weight of the releasing agent,        up to 30% by weight of the releasing agent, up to 35% by weight        of the releasing agent, up to 40% by weight of the releasing        agent, up to 45% by weight of the releasing agent, or up to 50%        by weight of the releasing agent.

50. The depot of any one of clauses 41 to 49, wherein the second controllayer is positioned between the first control layer and the therapeuticregion, and wherein the first control layer includes a first amount ofthe releasing agent and the second control layer includes a secondamount of the releasing agent, the second amount being at least 2×, atleast 3×, at least 4×, or at least 5× the first amount.

51. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/10 of a thickness ofthe therapeutic region.

52. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/12.5 of a thickness ofthe therapeutic region.

53. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/15 of a thickness ofthe therapeutic region.

54. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/17.5 of a thickness ofthe therapeutic region.

55. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/20 of a thickness ofthe therapeutic region.

56. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/22.5 of a thickness ofthe therapeutic region.

57. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/25 of a thickness ofthe therapeutic region.

58. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/30 of a thickness ofthe therapeutic region.

59. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/40 of a thickness ofthe therapeutic region.

60. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/50 of a thickness ofthe therapeutic region.

61. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/75 of a thickness ofthe therapeutic region.

62. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/100 of a thickness ofthe therapeutic region.

63. The depot of any one of the preceding clauses, wherein the depot isa flexible solid that is structurally capable of being handled by aclinician during the normal course of a surgery without breaking intomultiple pieces and/or losing its general shape.

64. The depot of any one of the preceding clauses, wherein the depot isconfigured to be placed in the knee of a patient and release theanalgesic in vivo for up to 7 days without breaking into multiplepieces.

65. The depot of any one of the preceding clauses, wherein the depot hasa width and a thickness, and wherein a ratio of the width to thethickness is 21 or greater.

66. The depot of clause 65, wherein the ratio is 30 or greater.

67. The depot of clause 65, wherein the ratio is 40 or greater.

68. The depot of any one of the preceding clauses, wherein the depot hasa surface area and a volume, and wherein a ratio of the surface area tovolume is at least 1.

69. The depot of any one of the preceding clauses, wherein the diffusionopenings include at least one or more pores and/or one or more channels.

70. The depot of any one of the preceding clauses, wherein the two ormore micro-thin layers of the bioresorbable polymer are bonded via heatcompression to form the therapeutic region.

71. The depot of any one of the preceding clauses, wherein the controlregion and the therapeutic region are bonded via heat compression.

72. The depot of any one of the preceding clauses, wherein the controlregion and the therapeutic region are thermally bonded.

73. The depot of any one of the preceding clauses, wherein dissolutionof the releasing agent following in vivo placement in the treatment sitecauses the control region and the therapeutic region to transition froma state of lesser porosity to a state of greater porosity to facilitatethe release of the analgesic from the depot.

74. The depot of any one of the preceding clauses, wherein the controlregion does not include the analgesic at least prior to implantation ofthe depot at the treatment site.

75. The depot of any one of clauses 1 to 73, wherein the control regioncomprises an analgesic different from the analgesic in the therapeuticregion.

76. The depot of any one of the preceding clauses, wherein thetherapeutic region does not include any releasing agent prior toimplantation of the depot at the treatment site.

77. The depot of any one of the preceding clauses, wherein the releasingagent is a first releasing agent and the therapeutic region includes asecond releasing agent mixed with the analgesic.

78. The depot of any one of clauses 1 to 77, wherein the releasing agentis a first releasing agent and the polymer is a first polymer, and thetherapeutic region includes a second releasing agent and a secondpolymer mixed with the analgesic.

79. The depot of any one of clauses 1 to 77, wherein the first releasingagent is the same as the second releasing agent.

80. The depot of any one of clauses 1 to 77, wherein the first releasingagent is the different than the second releasing agent.

81. The depot of any one of clauses 1 to 79, wherein a concentration ofthe first releasing agent within the control region is the greater thana concentration of the second releasing agent within the therapeuticregion.

82. The depot of any one of clauses 1 to 81, wherein a concentration ofthe first releasing agent within the control region is the less than aconcentration of the second releasing agent within the therapeuticregion.

83. The depot of any one of clauses 1 to 81, wherein a concentration ofthe first releasing agent within the control region is the same as aconcentration of the second releasing agent within the therapeuticregion.

84. The depot of any one of clauses 1 to 81, wherein a concentration ofthe first releasing agent within the control region is different than aconcentration of the second releasing agent within the therapeuticregion.

85. The depot of any one of the preceding clauses, wherein thetherapeutic region includes a plurality of microlayers.

86. The depot of any one of the preceding clauses, wherein the mass ofthe analgesic comprises at least 50% of the mass of the depot.

87. The depot of any one of the preceding clauses, wherein the ratio ofthe mass of the analgesic in the depot to the depot polymer mass is atleast 3:1.

88. The depot of any one of the preceding clauses, wherein the ratio ofthe mass of the analgesic in the depot to the depot polymer mass is atleast 4:1.

89. The depot of any one of the preceding clauses, wherein the ratio ofthe mass of the analgesic in the depot to the depot polymer mass is atleast 5:1.

90. The depot of any one of the preceding clauses, wherein a ratio ofthe mass of the analgesic in the depot to the depot polymer mass is atleast 6:1.

91. The depot of any one of the preceding clauses, wherein a ratio ofthe mass of the analgesic in the depot to the depot polymer mass is atleast 7:1.

92. The depot of any one of the preceding clauses, wherein a ratio ofthe mass of the analgesic in the depot to the depot polymer mass is atleast 8:1.

93. The depot of any one of the preceding clauses, wherein a ratio ofthe mass of the analgesic in the depot to the depot polymer mass is atleast 10:1.

94. The depot of any one of the preceding clauses, wherein a ratio ofthe mass of the analgesic in the depot to the depot polymer mass is atleast 16:1.

95. The depot of any one of the preceding clauses, wherein thetherapeutic region includes at least 60% by weight of the analgesic, 60%by weight of the analgesic, at least 70% by weight of the analgesic, atleast 80% by weight of the analgesic, at least 90% by weight of theanalgesic, or 100% by weight of the analgesic.

96. The depot of any one of the preceding clauses, wherein the depotincludes at least 15% by weight of the analgesic, at least 20% by weightof the analgesic, at least 30% by weight of the analgesic, at least 40%by weight of the analgesic, at least 50% by weight of the analgesic, atleast 60% by weight of the analgesic, at least 70% by weight of theanalgesic, at least 80% by weight of the analgesic, at least 90% byweight of the analgesic, or 100% by weight of the analgesic.

97. The depot of any one of the preceding clauses, wherein the analgesiccomprises at least one of: simple analgesics, local anesthetics, NSAIDsand opioids.

98. The depot of any one of the preceding clauses, wherein the analgesiccomprises a local anesthetic selected from at least one of bupivacaine,ropivacaine, mepivacaine, and lidocaine.

99. The depot of any one of the preceding clauses, further comprising anantibiotic, an antifungal, and/or an antimicrobial, wherein theantibiotic, the antifungal, and/or the antimicrobial is selected from atleast one of amoxicillin, amoxicillin/clavulanate, cephalexin,ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin,sulfamethoxazole/trimethoprim, tetracycline(s), minocycline,tigecycline, doxycycline, rifampin, triclosan, chlorhexidine,penicillin(s), aminoglycides, quinolones, fluoroquinolones, vancomycin,gentamycin, cephalosporin(s), carbapenems, imipenem, ertapenem,antimicrobial peptides, cecropin-mellitin, magainin, dermaseptin,cathelicidin, α-defensins, and α-protegrins, ketoconazole,clortrimazole, miconazole, econazole, intraconazole, fluconazole,bifoconazole, terconazole, butaconazole, tioconazole, oxiconazole,sulconazole, saperconazole, voriconazole, terbinafine, amorolfine,naftifine, griseofulvin, haloprogin, butenafine, tolnaftate, nystatin,cyclohexamide, ciclopirox, flucytosine, terbinafine, and amphotericin B.

100. The depot of any one of the preceding clauses, further comprisingan anti-inflammatory agent selected from at least one of steroids,prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone andmethylprednisolone, non-steroidal anti-inflammatory drugs (NSAIDs),aspirin, Ibuprofen, naproxen sodium, diclofenac, diclofenac-misoprostol,celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac,diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac,fenoprofen, flurbiprofen, ketorolac, meclofenamate, mefenamic acid, andCOX-2 inhibitors.

101. The depot of any one of the preceding clauses, wherein theanalgesic is dexamethasone.

102. The depot of any one of the preceding clauses, wherein theanalgesic is tetrodotoxin.

103. The depot of any one of the preceding clauses, wherein theanalgesic is saxitoxin.

104. The depot of any one of the preceding clauses, further comprisingat least one of: epinephrine, clonidine, transexamic acid.

105. The depot of any one of the preceding clauses, wherein thereleasing agent is a non-ionic surfactant.

106. The depot of any one of the preceding clauses, wherein thereleasing agent has hydrophilic properties.

107. The depot of any one of the preceding clauses, wherein thereleasing agent is a polysorbate.

108. The depot of any one of the preceding clauses, wherein thereleasing agent is Tween 20.

109. The depot of any one of clauses 1 to 107, wherein the releasingagent is Tween 80.

110. The depot of any one of the preceding clauses, wherein thereleasing agent is non-polymeric.

111. The depot of any one of the preceding clauses, wherein thereleasing agent is not a plasticizer.

112. The depot of any one of the preceding clauses, wherein the polymeris configured to degrade only after substantially all of the analgesichas been released from the depot.

113. The depot of any one of the preceding clauses, wherein the polymeris a copolymer.

114. The depot of any one of clauses 1 to 112, wherein the polymer is aterpolymer.

115. The depot of any one of the preceding clauses, wherein the polymerincludes at least one of polyglycolide (PGA), polycaprolactone (PCL),poly(DL-lactic acid) (PLA), poly(alpha-hydroxy acids),poly(lactide-co-glycolide)(PLGA or DLG),poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate)(PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), polyphosphate ester),poly(amino acid), polydepsipeptides, poly(butylene succinate) (PBS),polyethylene oxide, polypropylene fumarate, polyiminocarbonates,poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone)(PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid,poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide),poly(D,L-lactide-co-glycolide), poly(gycolide-trimethylene carbonate),poly(ethyl glutamate-co-glutamic acid),poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate),tyrosine-derived polycarbonate, poly 1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinatepolyphosphazene, polycaprolactone co-butylacrylate, a copolymer ofpolyhydroxybutyrate, a copolymer of maleic anhydride, a copolymer ofpoly(trimethylene carbonate), polyethylene glycol (PEG),hydroxypropylmethylcellulose and cellulose derivatives, polysaccharides(such as hyaluronic acid, chitosan and starch), proteins (such asgelatin and collagen) or PEG derivatives, polyaspirins,polyphosphagenes, collagen, starch, pre-gelatinized starch, hyaluronicacid, chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs,such as alpha tocopheryl acetate, d-alpha tocopheryl succinate,D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL),D,L-lactide-glycolide-caprolactone (DL-G-CL), dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), methacrylates, poly(N-isopropylacrylamide),PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG,PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucroseacetate isobutyrate)hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose orsalts thereof, Carbopol®, poly(hydroxyethylmethacrylate),poly(methoxyethylmethacrylate), poly(methoxyethoxy-ethylmethacrylate),polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol, andpoly(DL-lactide-co-glycolide-co-caprolactone).

116. The depot of any one of the preceding clauses, wherein the polymeris one of poly(DL-lactide-co-glycolide-co-caprolactone) andpoly(DL-lactide-co-glycolide)(PLGA).

117. The depot of any one of clauses 1 to 112, wherein the polymer ispoly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio of60:30:10.

118. The depot of any one of clauses 1 to 112, wherein the polymer ispoly(DL-lactide-co-glycolide)(PLGA) in a molar ratio of 50:50.

119. The depot of any one of the preceding clauses, wherein the polymeris ester-terminated.

120. The depot of any one of the preceding clauses, wherein the polymeris a terpolymer that includes three polymers selected from thefollowing: polyglycolide (PGA), polycaprolactone (PCL), poly(L-lacticacid) (PLA), poly(DL-lactic acid) (PLA), poly(trimethylene carbonate)(PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), and polyethylene glycol.

121. The depot of any one of the preceding clauses, wherein the polymeris a first polymer, and the therapeutic region includes a second polymermixed with the analgesic.

122. The depot of clause 121, wherein the first polymer and the secondpolymer are the same.

123. The depot of clause 121, wherein the first polymer and the secondpolymer are different.

124. The depot of any one of clauses 121 to 123, wherein the firstpolymer and/or the second polymer include at least one of polyglycolide(PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA),poly(alpha-hydroxy acids), poly(lactide-co-glycolide)(PLGA or DLG),poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate)(PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), polyphosphate ester),poly(amino acid), polydepsipeptides, poly(butylene succinate) (PBS),polyethylene oxide, polypropylene fumarate, polyiminocarbonates,poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone)(PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid,poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide),poly(D,L-lactide-co-glycolide), poly(gycolide-trimethylene carbonate),poly(ethyl glutamate-co-glutamic acid),poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate),tyrosine-derived polycarbonate, poly 1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinatepolyphosphazene, polycaprolactone co-butylacrylate, a copolymer ofpolyhydroxybutyrate, a copolymer of maleic anhydride, a copolymer ofpoly(trimethylene carbonate), polyethylene glycol (PEG),hydroxypropylmethylcellulose and cellulose derivatives, polysaccharides(such as hyaluronic acid, chitosan and starch), proteins (such asgelatin and collagen) or PEG derivatives, polyaspirins,polyphosphagenes, collagen, starch, pre-gelatinized starch, hyaluronicacid, chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs,such as alpha tocopheryl acetate, d-alpha tocopheryl succinate,D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL),D,L-lactide-glycolide-caprolactone (DL-G-CL), dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), methacrylates, poly(N-isopropylacrylamide),PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG,PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAM (sucroseacetate isobutyrate)hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose orsalts thereof, Carbopol®, poly(hydroxyethylmethacrylate),poly(methoxyethylmethacrylate), poly(methoxyethoxy-ethylmethacrylate),polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol,poly(DL-lactide-co-glycolide-co-caprolactone).

125. The depot of any one of clauses 121 to 123, wherein the firstpolymer and/or the second polymer is selected from the following:poly(DL-lactide-co-glycolide-co-caprolactone) andpoly(DL-lactide-co-glycolide)(PLGA).

126. The depot of any one of clauses 121 to 123, wherein the firstpolymer and/or the second polymer ispoly(DL-lactide-co-glycolide-co-caprolactone) and has a molar ratio of60:30:10.

127. The depot of any one of clauses 121 to 123, wherein the firstpolymer and/or the second polymer is poly(DL-lactide-co-glycolide) andhas a molar ratio of 50:50.

128. The depot of any one of clauses 121 to 127, wherein the firstpolymer and/or the second polymer is ester-terminated.

129. The depot of any one of clauses 121 to 123, wherein the firstpolymer and/or the second polymer is a terpolymer that includes threepolymers selected from the following: polyglycolide (PGA),polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(trimethylenecarbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), and polyethylene glycol.

130. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is no more than1:2.

131. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is no more than1:3.

132. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is no more than1:4.

133. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is no more than1:5.

134. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is no more than1:6.

135. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is no more than1:7.

136. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is no more than1:8.

137. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is no more than1:9.

138. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is no more than1:10.

139. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is no more than1:11.

140. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is at least 1:1.

141. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is at least 2:1.

142. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is at least 3:1.

143. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is at least 4:1.

144. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is at least 5:1.

145. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is at least 6:1.

146. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is at least 7:1.

147. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is at least 8:1.

148. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is at least 9:1.

149. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is at least 10:1.

150. The depot of any one of clauses 1 to 129, wherein the ratio of thereleasing agent to the polymer in the control region is at least 15:1.

151. The depot of any one of the preceding clauses, wherein:

-   -   the polymer is a first polymer and the therapeutic region        further includes a second polymer,    -   the depot has a depot polymer mass equivalent to a mass of the        first polymer plus a mass of the second polymer, and    -   a ratio of a mass of the analgesic in the depot to the depot        polymer mass is approximately 1:1.

152. The depot of clause 151, wherein the first polymer is the same asthe second polymer.

153. The depot of clause 151, wherein the first polymer is differentthan the second polymer.

154. The depot of any one of clauses 151 to 153, wherein the ratio ofthe mass of the analgesic in the depot to the depot polymer mass is atleast 2:1.

155. The depot of any one of clauses 151 to 153, wherein the ratio ofthe mass of the analgesic in the depot to the depot polymer mass is atleast 3:1.

156. The depot of any one of clauses 151 to 153, wherein the ratio ofthe mass of the analgesic in the depot to the depot polymer mass is atleast 4:1.

157. The depot of any one of clauses 151 to 153, wherein the ratio ofthe mass of the analgesic in the depot to the depot polymer mass isapproximately 5:1.

158. The depot of any one of clauses 151 to 153, wherein a ratio of themass of the analgesic in the depot to the depot polymer mass is at least6:1.

159. The depot of any one of clauses 151 to 153, wherein a ratio of themass of the analgesic in the depot to the depot polymer mass is at least7:1.

160. The depot of any one of clauses 151 to 153, wherein a ratio of themass of the analgesic in the depot to the depot polymer mass is at least8:1.

161. The depot of any one of clauses 151 to 153, wherein a ratio of themass of the analgesic in the depot to the depot polymer mass is at least10:1.

162. The depot of any one of clauses 151 to 153, wherein a ratio of themass of the analgesic in the depot to the depot polymer mass is at least16:1.

163. The depot of any one of the preceding clauses, wherein theanalgesic is a local anesthetic, and wherein the release of theanalgesic to the treatment site over the five days inhibits the growthof bacteria and fungi.

164. The depot of clause 163, wherein depot is configured to inhibit thegrowth of bacteria and fungi such that a number of bacteria on the depotis 10×, 20×, 30×, 40×, or 50× less than a number of bacteria present ona comparable depot containing no analgesic.

165. The depot of any one of the preceding clauses, wherein the releaseof analgesic is at a level sufficiently high to create a sensory block,thereby treating postoperative pain, but sufficiently low to avoid amotor block.

166. The depot of any one of the preceding clauses, wherein the releaseof the analgesic provides motor sparing relief from postoperative pain.

167. A depot for sustained, controlled release of a therapeutic agent,comprising:

-   -   a therapeutic region comprising the therapeutic agent;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in        contact with a fluid to form diffusion openings in the control        region; and    -   wherein, when the depot is placed in contact with a fluid, the        depot is configured to release the therapeutic agent into the        surrounding fluid for no less than 14 days, and    -   wherein about 20% to about 50% of the therapeutic agent is        released in the first about 3 to about 5 days of the 14 days,        and wherein at least 80% of the remaining therapeutic agent is        released in the last 11 days of the 14 days.

168. The depot of clause 167, wherein at least 85% of the remainingtherapeutic agent is released in the last 11 days of the 14 days.

169. The depot of clause 167, wherein at least 90% of the remainingtherapeutic agent is released in the last 11 days of the 14 days.

170. The depot of clause 167, wherein at least 95% of the remainingtherapeutic agent is released in the last 11 days of the 14 days.

171. The depot of any one of clauses 167 to 170, wherein no more than15% of the amount of therapeutic agent is released in the first 2 daysof the 14 days.

172. The depot of any one of clauses 167 to 170, wherein no more than20% of the amount of therapeutic agent is released in the first 2 daysof the 14 days.

173. The depot of any one of clauses 167 to 170, wherein no more than25% of the amount of therapeutic agent is released in the first 3 daysof the 14 days.

174. The depot of any one of clauses 167 to 170, wherein no more than30% of the amount of therapeutic agent is released in the first 3 daysof the 14 days.

175. The depot of any one of clauses 167 to 170, wherein the releasingagent is configured to dissolve when the depot is placed in contact withphosphate buffered saline to form diffusion openings.

176. A method for treating postoperative pain, comprising:

-   -   positioning a depot at a treatment site in vivo having        physiologic fluids, the depot comprising (a) a control region        including a bioresorbable polymer and a releasing agent mixed        with the polymer, and (b) a therapeutic region including at        least 50% by weight of an analgesic; and    -   releasing analgesic from the depot to the treatment site for no        less than seven days.

177. The method of clause 176, further comprising dissolving thereleasing agent at a first rate and degrading the polymer at a secondrate, wherein the first rate is greater than the second rate.

178. The method of clause 176 or clause 177, further comprisingdissolving the releasing agent in response to contact between thecontrol region and the physiologic fluids at the treatment site.

179. The method of any one of clauses 176 to 178, further comprisingcreating diffusion openings in the control region via the dissolution ofthe releasing agent in response to physiologic fluids at the treatmentsite.

180. The method of any one of clauses 176 to 179, wherein the releasingagent is a first releasing agent and the therapeutic region includes asecond releasing agent, and wherein the method further comprisescreating microchannels in the therapeutic region and the control regionvia dissolution of the first and/or second releasing agents.

181. The method of any one of clauses 176 to 180, wherein at least someof the microchannels penetrate both the therapeutic region and thecontrol region.

182. The method of any one of clauses 176 to 181, wherein thetherapeutic region comprises a plurality of microlayers, and wherein atleast some of the microchannels extend through consecutive microlayers.

183. The method of any one of clauses 176 to 159, wherein the controlregion comprises a first plurality of microlayers and the therapeuticregion comprises a second plurality of microlayers, and wherein at leastsome of the microchannels extend through the first and second pluralityof microlayers.

184. The method of any one of clauses 176 to 183, further includingincreasing a porosity of the depot via dissolution of the releasingagent.

185. The method of any one of clauses 176 to 184, wherein the analgesicis released one or more times in substantially discrete doses afterimplantation.

186. The method of any one of clauses 176 to 185, wherein the analgesicis released continuously for at least seven days after implantation.

187. The method of any one of clauses 176 to 186, wherein the analgesicis released for no less than 10 days.

188. The method of any one of clauses 176 to 186, wherein the analgesicis released for no less than 14 days.

189. The method of any one of clauses 176 to 188, wherein no more than20% of the amount of analgesic is released in the first day of the sevendays.

190. The method of any one of clauses 176 to 189, further comprisingsecuring the depot to the treatment site via an attachment means.

191. The method of any one of clauses 176 to 190, wherein the attachmentmeans is coupled to the depot prior to implantation.

192. The method of any one of clauses 176 to 191, wherein the depot is afirst depot and the method further comprises positioning a second depotat the treatment site.

193. The method of clause 192, wherein the first and second depotstogether release at least 1400 mg of the analgesic to the treatment siteover a period of no less than seven days.

194. A method for treating postoperative pain associated with orthopedicsurgery with any of the depots of clauses 1 to 175, 225 to 227, and 273to 429 and/or systems of clauses 211 to 224.

195. A method for treating postoperative pain in a patient followingorthopedic surgery, the method comprising:

-   -   implanting a plurality of depots at a site of the surgery, each        of the depots comprising (a) a control region including a        bioresorbable polymer and a releasing agent mixed with the        polymer, and (b) a therapeutic region including at least 50% by        weight of an analgesic; and    -   releasing analgesic from the depot to the site for no less than        seven days.

196. A method for treating postoperative pain in a patient followingorthopedic surgery, the method comprising:

-   -   implanting a depot at a site of the surgery, the depot        comprising (a) a control region including a bioresorbable        polymer and a releasing agent mixed with the polymer, and (b) a        therapeutic region including at least 50% by weight of an        analgesic; and    -   releasing analgesic from the depot to the site for no less than        seven days.

197. A method for treating postoperative pain in a patient followingtotal knee arthroplasty, comprising:

-   -   positioning a depot in a knee of the patient, the depot        comprising (a) a control region including a bioresorbable        polymer and a releasing agent mixed with the polymer, and (b) a        therapeutic region including at least 50% by weight of an        analgesic; and    -   releasing analgesic from the depot to the patient's knee for no        less than seven days.

198. The method of clause 197, wherein the depot is any of the depots ofclauses 1 to 175, 225 to 227, and 273 to 429.

199. The method of clause 197 or clause 198, wherein positioning thedepot comprises placing at least one depot in at least one of:suprapatellar pouch, lateral gutter, medial gutter, posterior capsule,quadricep tendon, skin incision, arthrotomy, adductor canal, saphenousnerve, genicular nerve.

200. The method of any one of clauses 197 to 199, wherein positioningthe depot comprises positioning at least one depot adjacent at least oneof a saphenous nerve, an adductor canal, and a femoral nerve.

201. The method of any one of clauses 197 to 200, wherein positioningthe depot comprises positioning at least one depot at or near one ormore nerves innervating all or a portion of an anterior knee capsule.

202. The method of any one of clauses 197 to 201, wherein positioningthe depot comprises positioning at least one depot at or near at or neara superolateral genicular branch from the vastus lateralis, asuperomedial genicular branch from the vastus medialis, a medialgenicular branch from the vastus intermedius, an inferolateral genicularbranch from the common peroneal nerve, an inferomedial genicular branchfrom the saphenous nerve, and/or a lateral genicular branch from thecommon peroneal nerve.

203. The method of any one of clauses 197 to 200, wherein positioningthe depot comprises intracapsular placement of at least one depot.

204. The method of any one of clauses 197 to 203, wherein positioningthe depot comprises extracapsular placement of at least one depot.

205. The method of any one of clauses 197 to 204, wherein positioningthe depot comprises intracapsular placement without interfering witharticulation of the knee.

206. The method of clause 205, wherein placing at least one depot at atleast one of: suprapatellar pouch, lateral gutter, medial gutter,posterior capsule, quadricep tendon, skin incision, arthrotomy, adductorcanal.

207. A system for treating postoperative pain associated with orthopedicsurgery, the system comprising:

-   -   a plurality of depots, each of which is any of the depots        described in the previous clauses, wherein the plurality of        depots are configured to be implanted at a treatment site of a        patient and release the analgesic to the treatment site.

208. The system of clause 207, wherein the depots are configured torelease analgesic to the treatment site for at least 7 days, at least 8days, at least 9 days, at least 10 days, at least 11 days, at least 12days, at least 13 days, or at least 14 days.

209. The system of clause 208, wherein the depots are configured tocollectively release no more than 250 mg of analgesic per day within thefirst 3 days, and no more than 150 mg per day in the remaining days.

210. A system for treating postoperative pain, comprising:

-   -   a delivery system; and    -   a depot configured to be implanted at a treatment site in vivo        with the delivery system, wherein the depot comprises any of the        depots of clauses 1 to 175, 225 to 227, and 273 to 429.

211. A system for treating postoperative pain, comprising:

-   -   an attachment means; and    -   a depot configured to be implanted at a treatment site in vivo        and secured at the treatment site via the attachment means,        wherein the depot comprises any of the depots of clauses 1 to        175, 225 to 227, and 273 to 429.

212. The system of clause 187, wherein the attachment means is coupledto the depot prior to implantation.

213. The system of clause 187 or clause 212, wherein the attachmentmeans is at least one of a suture, a tine, a barb, a hook, and a screw.

214. The system of any one of clauses 211 to 213, wherein the pain isassociated with orthopedic surgery.

215. The system of any one of clauses 211 to 214, wherein the pain isassociated with joint replacement surgery.

216. The system of any one of clauses 211 to 215, wherein the pain isassociated with a knee replacement surgery.

217. The system of any one of clauses 211 to 215, wherein the pain isassociated with a partial knee replacement surgery.

218. The system of any one of clauses 211 to 215, wherein the pain isassociated with a total knee replacement surgery.

219. The system of any one of clauses 211 to 215, wherein the pain isassociated with a revision surgery of a knee replacement surgery.

220. The system of any one of clauses 211 to 219, wherein the depot isconfigured to be positioned adjacent at least one of a saphenous nerve,an adductor canal, and a femoral nerve.

221. The system of any one of clauses 211 to 220, wherein the depot isconfigured to be positioned adjacent at least one of a posterior capsuleof the knee, a superior region of the patella, or an incision into theknee capsule.

222. The system of any one of clauses 211 to 191, wherein the depot isconfigured to be positioned within the knee capsule within the medialand/or lateral gutters.

223. A system for treating postoperative pain, comprising a deliverysystem and any of the depots of clauses 1 to 175, 225 to 227, and 273 to429.

224. A system for treating postoperative pain, comprising a plurality ofdepots, any of which comprising any of the depots of clauses 1 to 175,225 to 227, and 273 to 429.

225. A depot for the release of a therapeutic agent to treat or manage aparticular condition or disease, comprising:

-   -   a therapeutic region comprising the therapeutic agent and a        bioresorbable polymer carrier;    -   a control region comprising a bioresorbable polymer layer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve over a first period of time        following in vivo placement to form diffusion openings in the        control region; and    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the therapeutic agent        at the treatment site for a second period of time;    -   wherein the second period of time is greater than the first        period of time;    -   wherein following the second period of time the polymer carrier        of the therapeutic region and the polymer layer of the control        region comprise a highly porous polymer structure configured to        degrade in vivo without core acidification.

226. The depot of clause 225, wherein the highly porous polymerstructure at the end of the second period of time has a mass that is nogreater than 50% of the mass of the depot prior to in vivo placement.

227. The depot of clause 225 or clause 226, wherein the highly porouspolymer structure is configured to degrade in vivo via surface erosion.

228. A method for treating postoperative pain following a non-orthopedicsurgical procedure, comprising:

-   -   positioning a depot at a treatment site in vivo having        physiologic fluids, the depot comprising (a) a control region        including a bioresorbable polymer and a releasing agent mixed        with the polymer, and (b) a therapeutic region including at        least 50% by weight of an analgesic;    -   dissolving the releasing agent in response to contact between        the releasing agent and the physiologic fluids, thereby forming        diffusion openings in the control region; and    -   releasing analgesic through the diffusion openings from the        therapeutic region to the treatment site for no less than five        days.

229. The method of clause 228, wherein the surgical procedure comprisesat least one of: a thoracotomy, an esophageal surgery, a cardiacsurgery, a lung resection, or a thoracic surgery.

230. The method of clause 229, wherein the treatment site comprises athoracic paravertebral space.

231. The method of clause 229 or clause 230, wherein the analgesicreleased from the depot at least partially blocks an intercostal nerve.

232. The method of clause 228, wherein the surgical procedure comprisesat least one of: a mastectomy, a breast augmentation, a breastreduction, or a breast reconstruction.

233. The method of clause 232, wherein the treatment site comprises aninfraclavicular space.

234. The method of clause 232 or clause 233, wherein the analgesicreleased from the depot at least partially blocks at least one of: anintercostal nerve, a medial pectoral nerve, or a lateral pectoral nerve.

235. The method of clause 228, wherein the surgical procedure comprisesat least one of: a myomectomy, a Caesarean section, a hysterectomy, anoophorectomy, or a pelvic floor reconstruction.

236. The method of clause 228, wherein the surgical procedure comprisesat least one of: a proctocolectomy, a pancreatectomy, an appendectomy, ahemorrhoidectomy, a cholecystectomy, a kidney transplant, a nephrectomy,a radical prostatectomy, a gastrectomy, a small bowel resection, asplenectomy, an incisional hernia repair, an inguinal hernia repair, asigmoidectomy, a liver resection, an enterostomy, a rectum resection, akidney stone removal, or a cystectomy.

237. The method of clause 236, wherein the analgesic released from thedepot at least partially blocks a nerve at or adjacent to a transverseabdominis plane.

238. The method of clause 228, wherein the surgical procedure comprisesat least one of: a tonsillectomy, a submucosal resection, a rhinoplasty,a sinus surgery, an inner ear surgery, a parotidectomy, or asubmandibular gland surgery.

239. The method of clause 228, wherein the surgical procedure comprisesat least one of: a dentoalveolar surgery, a dental implant, anorthognathic surgery, a temporomandibular joint (TMJ) surgery, or anoral reconstruction surgery.

240. The method of clause 228, wherein the surgical procedure comprisesa tumor resection.

241. The method of clause 228, wherein the surgical procedure comprisesliposuction.

242. The method of any one of clauses 228 to 241, further comprisingdissolving the releasing agent at a first rate and degrading the polymerat a second rate, wherein the first rate is greater than the secondrate.

243. The method of any one of clauses 228 to 242, wherein the analgesicis released for no less than 10 days.

244. The method of any one of clauses 228 to 243, wherein the analgesicis released for no less than 14 days.

245. The method of any one of clauses 228 to 244, wherein no more than20% of the amount of analgesic is released in the first day of the fivedays.

246. The method of any one of clauses 228 to 245, further comprisingsecuring the depot to the treatment site via an attachment means.

247. The method of clause 246, wherein the attachment means is coupledto the depot prior to implantation.

248. The method of any one of clauses 228 to 248, wherein the depot is afirst depot and the method further comprises positioning a second depotat the treatment site.

249. The method of clause 248, wherein the first and second depotstogether release at least 1400 mg of the analgesic to the treatment siteover a period of no less than seven days.

250. The method of any one of clauses 228 to 254, wherein no more than400 mg of the therapeutic agent is released within any day of the fivedays.

251. A method for treating postoperative pain following a non-orthopedicsurgical procedure, comprising:

-   -   positioning a depot at a treatment site in vivo having        physiologic fluids, the depot comprising (a) a control region        including a bioresorbable polymer and a releasing agent mixed        with the polymer, and (b) a therapeutic region including at        least 50% by weight of an analgesic; and    -   releasing analgesic from the depot to the treatment site for no        less than five days.

252. The method of clause 251, wherein the surgical procedure comprisesat least one of: a thoracotomy, an esophageal surgery, a cardiacsurgery, a lung resection, or a thoracic surgery.

253. The method of clause 252, wherein the treatment site comprises athoracic paravertebral space.

254. The method of clause 252 or 253, wherein the analgesic releasedfrom the depot at least partially blocks an intercostal nerve.

255. The method of clause 251, wherein the surgical procedure comprisesat least one of: a mastectomy, a breast augmentation, a breastreduction, or a breast reconstruction.

256. The method of clause 255, wherein the treatment site comprises aninfraclavicular space.

257. The method of clause 255 or 256, wherein the analgesic releasedfrom the depot at least partially blocks at least one of: an intercostalnerve, a medial pectoral nerve, or a lateral pectoral nerve.

258. The method of clause 251, wherein the surgical procedure comprisesat least one of: a myomectomy, a caesarean section, a hysterectomy, anoophorectomy, or a pelvic floor reconstruction.

259. The method of clause 251, wherein the surgical procedure comprisesat least one of: a proctocolectomy, a pancreatectomy, an appendectomy, ahemorrhoidectomy, a cholecystectomy, a kidney transplant, a nephrectomy,a radical prostatectomy, a gastrectomy, a small bowel resection, asplenectomy, an incisional hernia repair, an inguinal hernia repair, asigmoidectomy, a liver resection, an enterostomy, a rectum resection, akidney stone removal, or a cystectomy.

260. The method of clause 259, wherein the analgesic released from thedepot at least partially blocks a nerve at or adjacent to a transverseabdominis plane.

261. The method of clause 251, wherein the surgical procedure comprisesat least one of: a tonsillectomy, a submucosal resection, a rhinoplasty,a sinus surgery, an inner ear surgery, a parotidectomy, or asubmandibular gland surgery.

262. The method of clause 251, wherein the surgical procedure comprisesat least one of: a dentoalveolar surgery, a dental implant, anorthognathic surgery, a temporomandibular joint (TMJ) surgery, or anoral reconstruction surgery.

263. The method of clause 251, wherein the surgical procedure comprisesa tumor resection.

264. The method of clause 251, wherein the surgical procedure comprisesliposuction.

265. A method for treating postoperative pain following a surgicalprocedure involving a patient's chest, the method comprising:

-   -   positioning a depot proximate to an intercostal nerve at a        treatment site having physiologic fluids, the depot        comprising (a) a control region including a bioresorbable        polymer and a releasing agent mixed with the polymer, and (b) a        therapeutic region including at least 50% by weight of an        analgesic; and    -   releasing analgesic from the depot to the intercostal nerve for        no less than five days.

266. The method of clause 265, wherein the surgical procedure comprisesat least one of: a thoracotomy, an esophageal surgery, a cardiacsurgery, a lung resection, or a thoracic surgery.

267. The method of clause 265 or 266, wherein the treatment sitecomprises a thoracic paravertebral space.

268. A method for treating postoperative pain following a surgicalprocedure involving a patient's breast, the method comprising:

-   -   positioning a depot proximate to an intercostal and/or pectoral        nerve at a treatment site having physiologic fluids, the depot        comprising (a) a control region including a bioresorbable        polymer and a releasing agent mixed with the polymer, and (b) a        therapeutic region including at least 50% by weight of an        analgesic; and    -   releasing analgesic from the depot to the intercostal and/or        pectoral nerve for no less than five days.

269. The method of clause 268, wherein the surgical procedure comprisesat least one of: a mastectomy, a breast augmentation, a breastreduction, or a breast reconstruction.

270. The method of clause 268 or 269, wherein the treatment sitecomprises an intraclavicular space.

271. A method for treating postoperative pain following a general,abdominal, or urological surgical procedure, the method comprising:

-   -   positioning a depot proximate to a transverse abdominis plane at        a treatment site having physiologic fluids, the depot        comprising (a) a control region including a bioresorbable        polymer and a releasing agent mixed with the polymer, and (b) a        therapeutic region including at least 50% by weight of an        analgesic; and    -   releasing analgesic from the depot to the intercostal and/or        pectoral nerve for no less than five days.

272. The method of clause 271, wherein the surgical procedure comprisesat least one of: a proctocolectomy, a pancreatectomy, an appendectomy, ahemorrhoidectomy, a cholecystectomy, a kidney transplant, a nephrectomy,a radical prostatectomy, a gastrectomy, a small bowel resection, asplenectomy, an incisional hernia repair, an inguinal hernia repair, asigmoidectomy, a liver resection, an enterostomy, a rectum resection, akidney stone removal, or a cystectomy.

273. A depot for sustained, controlled release of a therapeutic agent,the depot comprising:

-   -   a therapeutic region comprising the therapeutic agent; and    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured such that, following submersion        of the depot in buffer solution for seven days, the flexural        strength of the depot decreases by no more than 75%.

274. The depot of clause 273, wherein the depot is configured such that,following submersion of the depot in buffer solution for seven days, theflexural strength of the depot decreases by no more than 70%.

275. The depot of clause 273, wherein the depot is configured such that,following submersion of the depot in buffer solution for seven days, theflexural strength of the depot decreases by no more than 65%.

276. The depot of clause 273, wherein the depot is configured such that,following submersion of the depot in buffer solution for seven days, theflexural strength of the depot decreases by no more than 60%.

277. The depot of clause 273, wherein the depot is configured such that,following submersion of the depot in buffer solution for seven days, theflexural strength of the depot decreases by no more than 55%.

278. The depot of clause 273, wherein the depot is configured such that,following submersion of the depot in buffer solution for seven days, theflexural strength of the depot decreases by no more than 50%.

279. The depot of clause 273, wherein the depot is configured such that,following submersion of the depot in buffer solution for seven days, theflexural strength of the depot decreases by no more than 45%.

280. A depot for sustained, controlled release of a therapeutic agent,the depot comprising:

-   -   a therapeutic region comprising the therapeutic agent; and    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured such that, following submersion        of the depot in buffer solution until approximately 75% of the        therapeutic agent by weight has been released, the flexural        strength of the depot decreases by no more than 75%.

281. The depot of clause 280, wherein the depot is configured such that,following submersion of the depot in buffer solution until approximately75% of the therapeutic agent by weight has been released, the flexuralstrength of the depot decreases by no more than 70%.

282. The depot of clause 280, wherein the depot is configured such that,following submersion of the depot in buffer solution until approximately75% of the therapeutic agent by weight has been released, the flexuralstrength of the depot decreases by no more than 65%.

283. The depot of clause 280, wherein the depot is configured such that,following submersion of the depot in buffer solution until approximately75% of the therapeutic agent by weight has been released, the flexuralstrength of the depot decreases by no more than 60%.

284. The depot of clause 280, wherein the depot is configured such that,following submersion of the depot in buffer solution until approximately75% of the therapeutic agent by weight has been released, the flexuralstrength of the depot decreases by no more than 55%.

285. The depot of clause 280, wherein the depot is configured such that,following submersion of the depot in buffer solution until approximately75% of the therapeutic agent by weight has been released, the flexuralstrength of the depot decreases by no more than 50%.

286. The depot of clause 280, wherein the depot is configured such that,following submersion of the depot in buffer solution until approximately75% of the therapeutic agent by weight has been released, the flexuralstrength of the depot decreases by no more than 45%.

287. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 14 days, and    -   wherein about 20% to about 40% of the analgesic is released in        the first 3 days of the 14 days, and wherein at least 80% of the        remaining analgesic is released in the last 11 days of the 14        days.

288. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days, and    -   wherein the control region does not include the analgesic at        least prior to implantation of the depot at the treatment site.

289. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region; and    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days,    -   wherein the control region comprises an analgesic different from        the analgesic in the therapeutic region.

290. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days, and    -   wherein the releasing agent is a first releasing agent and the        therapeutic region includes a second releasing agent mixed with        the analgesic.

291. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days, and    -   wherein the releasing agent is a first releasing agent and the        polymer is a first polymer, and the therapeutic region includes        a second releasing agent and a second polymer mixed with the        analgesic.

292. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days, and    -   wherein a thickness of the control region is less than or equal        to 1/10, 1/12.5, 1/15, 1/17.5, 1/20, 1/22.5, 1/25, 1/30, 1/40,        1/50, 1/60, 1/70, 1/80, 1/90, or 1/100 of a thickness of the        therapeutic region.

293. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days, and    -   wherein a thickness of the control region is less than or equal        to 1/75 of a thickness of the therapeutic region.

294. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days, and    -   wherein a thickness of the control region is less than or equal        to 1/100 of a thickness of the therapeutic region.

295. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic; and    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region,    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days, and    -   wherein the first control layer includes a first amount of the        releasing agent and the second control layer includes a second        amount of the releasing agent different than the first amount.

296. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days,    -   wherein the depot has a total surface area comprising the        exposed surface area of the cover region plus the exposed        surface area of the therapeutic region, and    -   wherein, when the depot is initially positioned at the treatment        site in vivo, a ratio of the exposed surface area of the        therapeutic region to the exposed surface area of the cover        region is from about 5% to about 20%, or from about 5% to about        15%, or from about 5% to about 10%.

297. A depot for the controlled, sustained release of a therapeuticagent, comprising:

-   -   a therapeutic region comprising the therapeutic agent, the        therapeutic region elongated along a first axis; and    -   a control region at least partially surrounding the therapeutic        region and elongated along the first axis, the control region        comprising a bioresorbable polymer and a releasing agent mixed        with the polymer, wherein the releasing agent is configured to        dissolve when the depot is placed in vivo to form diffusion        openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the therapeutic agent        at the treatment site for a period of time not less than 3 days.

298. The depot of any one of the preceding clauses, wherein the depot isat least 5 times longer along the first axis than a maximum transversedimension along a second axis orthogonal to the first.

299. The depot of any one of the preceding clauses, wherein the depot isat least 10 times longer along the first axis than a maximum transversedimension along a second axis orthogonal to the first.

300. The depot of any one of the preceding clauses, wherein the depot issubstantially columnar.

301. The depot of any one of the preceding clauses, wherein the depot issubstantially cylindrical.

302. The depot of any one of the preceding clauses, wherein thetherapeutic region is substantially cylindrical.

303. The depot of any one of the preceding clauses, further comprisingat least one opening extending through the therapeutic region.

304. The depot of any one of the preceding clauses, wherein the openingforms a cylindrical lumen extending parallel to the first axis.

305. The depot of any of the preceding clauses, wherein the openingcomprises a lumen extending along a second axis substantiallyperpendicular to the first axis.

306. The depot of any of the preceding clauses, further comprising aplurality of elongated openings extending parallel to the second axis.

307. The depot of any one of the preceding clauses, wherein thetherapeutic region comprises a plurality of separate elongatedsub-regions extending substantially parallel to the first axis.

308. The depot of any one of the preceding clauses, wherein each of theelongated sub-regions is substantially cylindrical.

309. The depot of any one of the preceding clauses, wherein each of theelongated sub-regions are radially separated from one another by thecontrol region.

310. The depot of any one of the preceding clauses, wherein a radiallyoutermost dimension of the depot varies along the first axis.

311. The depot of any one of the preceding clauses, wherein a radiallyoutermost dimension of the therapeutic region varies along the firstaxis.

312. The depot of any one of the preceding clauses, wherein thetherapeutic region is a series of separate regions, covered by andconnected by a continuous control region.

313. The depot of the preceding clauses, wherein the control region isnarrower in the regions without an internal therapeutic region.

314. The depot of the preceding clauses, wherein the control region isdesigned to bend or break during or after delivery.

315. The depot of any one of the preceding clauses, wherein the controlregion has a variable thickness along a length of the depot along thefirst axis.

316. The depot of any one of the preceding clauses, wherein the controlregion has a thickness that varies radially around the first axis.

317. The depot of any one of the preceding clauses, wherein the variablethickness of the control region causes the depot to curve or bend whendeployed in vivo.

318. The depot of any one of the preceding clauses, wherein the depot isconfigured to curve or bend preferentially when placed in contact withphysiological fluids in vivo.

319. The depot of any one of the preceding clauses, wherein the depotcomprises an elongated polymer strip having a length between itslongitudinal ends and a width between lateral edges, the length greaterthan the width, and wherein the depot has a preset shape in an expandedconfiguration in which the strip is curled about an axis with the widthof the strip facing the axis, thereby forming a ring-like shape.

320. The depot of any one of the preceding clauses, wherein the depotforms an annular or semi-annular shape.

321. The depot of any one of the preceding clauses, wherein the depothas a first region and a second region, each extending longitudinallyand coextensive with one another over all or a portion of theirrespective lengths, the first region having a first elasticity and thesecond region having a second elasticity less than the first elasticity.

322. The depot of the preceding clause, wherein the depot has beenstretched beyond the elastic hysteresis point of the second region suchthat, when released from a delivery device, the depot transitions from astraightened state to a curved state in which the second region pullsthe depot into the curved shape.

323. The depot of any one of the preceding clauses, wherein the depothas a first region and a second region, each extending longitudinallyand coextensive with one another over all or a portion of theirrespective lengths, the first region being more hydrophilic than thesecond region.

324. The depot of the preceding clause, wherein, when released from adelivery device, the depot transitions from a straightened state to acurved state in which the second region pulls the depot into the curvedshape.

325. The depot of any one of the preceding clauses, wherein the controlregion has first and second portions having a first thickness, the firstand second portions separated along the first axis by a third portionhaving a second thickness different from the first.

326. The depot of any one of the preceding clauses, wherein the depotextends along the first axis from a first end to a second end, andwherein the control region has a thickness that increases from the firstend to the second end.

327. The depot of any one of the preceding clauses, wherein the depotextends along the first axis from a first end to a second end, andwherein the control region does not cover the therapeutic region at thefirst end of the depot.

328. The depot of any one of the preceding clauses, wherein the depotextends along the first axis from a first end to a second end, andwherein the control region does not cover the therapeutic region at thefirst end or the second end.

329. The depot of any one of the preceding clauses, wherein the controlregion has a plurality of discrete openings formed therein.

330. The depot of any one of the preceding clauses, wherein the controlregion has an opening elongated along the first axis.

331. The depot of any one of the preceding clauses, wherein theelongated opening in the control region extends along the entire lengthof the depot.

332. The depot of any one of the preceding clauses, wherein the controlregion comprises a plurality of circular apertures formed therein.

333. The depot of any one of the preceding clauses, wherein thetherapeutic region is a first therapeutic region, the depot furthercomprising a second therapeutic region, each of the first and secondtherapeutic regions being elongated along the first axis, wherein thefirst and second therapeutic regions are configured to release thetherapeutic agent at different rates.

334. The depot of any one of the preceding clauses, wherein thetherapeutic region is a first therapeutic region, the depot furthercomprising a second therapeutic region, each of the first and secondtherapeutic regions being elongated along the first axis, wherein thefirst and second therapeutic regions comprise different therapeuticagents.

335. The depot of any one of the preceding clauses, wherein the firstand second therapeutic regions are coaxially aligned.

336. The depot of any one of the preceding clauses, wherein the firstand second therapeutic regions extend parallel to one another along alength of the depot.

337. The depot of any one of the preceding clauses, further comprising abarrier region configured to dissolve in vivo more slowly than thecontrol region or the therapeutic region.

338. The depot of any one of the preceding clauses, further comprising abarrier region configured to slow the passage of physiological fluids invivo therethrough to the control region or the therapeutic region.

339. The depot of any one of the preceding clauses, wherein the barrierregion is disposed coaxially with the therapeutic region, such that thecontrol region at least partially surrounds both the therapeutic regionand the barrier region.

340. The depot of any one of the preceding clauses, wherein the barrierregion is a first barrier region, the depot further comprising a secondbarrier region, the first and second barrier regions separated axiallyfrom one another by the therapeutic region.

341. The depot of any one of the preceding clauses, wherein the firstand second barrier regions have different dimensions.

342. The depot of any one of the preceding clauses, wherein the barrierregion is disposed coaxially with the control region, such that thecontrol region and barrier region together at least partially surroundthe therapeutic region.

343. The depot of any one of the preceding clauses, wherein the firstand second barrier regions are separated axially from one another by thecontrol region.

344. The depot of any one of the preceding clauses, wherein the depotextends along the first axis from a first end to a second end, andwherein the barrier region is disposed over the first end of the depot.

345. The depot of any one of the preceding clauses, wherein the depotextends along the first axis from a first end to a second end, andwherein the barrier region comprises a first end cap disposed over thefirst end of the depot and a second end cap disposed over the second endof the depot.

346. The depot of any one of the preceding clauses, wherein thetherapeutic region comprises a covered portion and an exposed portion,wherein the covered portion is covered by the control region such that,when the depot is initially positioned at the treatment site in vivo,the control region is between the covered portion of the therapeuticregion and physiologic fluids at the treatment site and the exposedportion of the therapeutic region is exposed to the physiologic fluids.

347. The depot of any one of the preceding clauses, wherein thetherapeutic agent in the therapeutic region comprises at least 50% ofthe total weight of the depot.

348. The depot of any one of the preceding clauses, wherein the periodof time is not less not less than 7 days, than 15 days, not less than 30days, not less than 45 days, not less than 60 days, or not less than 90days.

349. The depot of any one of the preceding clauses, wherein about 40% toabout 60% of the therapeutic agent in the therapeutic region is releasedin the first half of the period of time.

350. The depot of any one of the preceding clauses, wherein at least 90%of the therapeutic agent in the therapeutic region is released withinthe period of time.

351. The depot of any one of the preceding clauses, wherein the depot isconfigured to release about 2 μg to about 5 mg of the therapeutic agentto the treatment site per day.

352. The depot of any one of the preceding clauses, wherein the depot isconfigured to release the therapeutic agent at the treatment site invivo for no less than 8 days, no less than 9 days, no less than 10 days,no less than 11 days, no less than 12 days, no less than 13 days, noless than 14 days, no less than 15 days, no less than 16 days, no lessthan 17 days, no less than 18 days, no less than 19 days, no less than20 days, no less than 21 days, no less than 22 days, no less than 23days, no less than 24 days, no less than 25 days, no less than 26 days,no less than 27 days, no less than 28 days, no less than 29 days, noless than 30 days, no less than 40 days, no less than 50 days, no lessthan 60 days, no less than 70 days, no less than 90 days, no less than100 days, no less than 200 days, no less than 300 days, or no less than365 days.

353. The depot of any one of the preceding clauses, wherein thetherapeutic agent is released at a substantially steady state ratethroughout the period of time.

354. The depot of any one of the preceding clauses, wherein,

-   -   the depot has a total surface area comprising the exposed        surface area of the control region plus the exposed surface area        of the therapeutic region, and    -   when the depot is initially positioned at the treatment site in        vivo, a ratio of the exposed surface area of the therapeutic        region to the exposed surface area of the control region is from        about 5% to about 20%, or from about 5% to about 15%, or from        about 5% to about 10%.

355. The depot of any one of the preceding clauses, wherein the exposedsurface area of the control region is less than the exposed surface areaof the therapeutic region.

356. The depot of any one of the preceding clauses, wherein the exposedsurface area of the control region is greater than the exposed surfacearea of the therapeutic region.

357. The depot of any one of the preceding clauses, wherein the controlregion is a first control region, and wherein the depot comprises asecond control region.

358. The depot of any one of the preceding clauses, wherein the firstcontrol region is disposed at a first side of the therapeutic region andthe second control region is disposed at a second side of thetherapeutic region opposite the first side.

359. The depot of any one of the preceding clauses, wherein the depotcomprises a plurality of control regions and a plurality of therapeuticregions, and wherein each of the therapeutic regions is separated froman adjacent one of the therapeutic regions by one or more controlregions.

360. The depot of any one of the preceding clauses, wherein the depotcomprises from about 2 to about 10 therapeutic regions.

361. The depot of any one of the preceding clauses, wherein the controlregion comprises a first control layer and a second control layer.

362. The depot of any one of the preceding clauses, wherein the secondcontrol layer is adjacent to the therapeutic region and the firstcontrol layer encapsulates/encloses the therapeutic region and thesecond control layer.

363. The depot of any one of the preceding clauses, wherein the firstcontrol layer and the second control layer together enclose thetherapeutic region.

364. The depot of any one of the preceding clauses, wherein the firstcontrol layer comprises a first plurality of sub-layers and the secondcontrol layer comprises a second plurality of sub-layers.

365. The depot of any one of the preceding clauses, wherein the firstcontrol layer includes a first amount of the releasing agent and thesecond control layer includes a second amount of the releasing agentdifferent than the first amount.

366. The depot of any one of the preceding clauses, wherein the secondcontrol layer is positioned between the first control layer and thetherapeutic region, and wherein the first control layer includes a firstconcentration of the releasing agent and the second control layerincludes a second concentration of the releasing agent greater than thefirst concentration.

367. The depot of any one of the preceding clauses, wherein the secondcontrol layer is positioned between the first control layer and thetherapeutic region, and wherein the first control layer includes a firstconcentration of the releasing agent and the second control layerincludes a second concentration of the releasing agent less than thefirst concentration.

368. The depot of any one of the preceding clauses, wherein the secondcontrol layer is positioned between the first control layer and thetherapeutic region, and wherein

-   -   the first control layer includes up to 5% by weight of the        releasing agent, up to 10% by weight of the releasing agent, up        to 15% by weight of the releasing agent, up to 20% by weight of        the releasing agent, up to 25% by weight of the releasing agent,        up to 30% by weight of the releasing agent, up to 35% by weight        of the releasing agent, up to 40% by weight of the releasing        agent, up to 45% by weight of the releasing agent, or 50% by        weight of the releasing agent; and    -   the second control layer includes up to 5% by weight of the        releasing agent, up to 10% by weight of the releasing agent, up        to 15% by weight of the releasing agent, up to 20% by weight of        the releasing agent, up to 25% by weight of the releasing agent,        up to 30% by weight of the releasing agent, up to 35% by weight        of the releasing agent, up to 40% by weight of the releasing        agent, up to 45% by weight of the releasing agent, or up to 50%        by weight of the releasing agent.

369. The depot of any one of the preceding clauses, wherein the secondcontrol layer is positioned between the first control layer and thetherapeutic region, and wherein the first control layer includes a firstamount of the releasing agent and the second control layer includes asecond amount of the releasing agent, the second amount being at least2×, at least 3×, at least 4×, or at least 5× the first amount.

370. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/10, 1/12.5, 1/15,1/17.5, 1/20, 1/22.5, 1/25, 1/27.5, 1/30, 1/32.5, 1/35, 1/37.5, 1/40,1/42.5, 1/45, 1/47.5, 1/50, 1/55, 1/60, 1/65, 1/70, 1/75, 1/80, 1/85,1/90, 1/95, or 1/100 of a thickness of the therapeutic region.

371. The depot of any one of the preceding clauses, wherein the depotcomprises an elongate columnar structure configured to be implanted in apatient.

372. The depot of any one of the preceding clauses, wherein the depotcomprises one of a plurality of beads or microspheres.

373. The depot of any one of the preceding clauses, wherein the beads ormicrospheres have varying release profiles.

374. The depot of any one of the preceding clauses, wherein the beads ormicrospheres comprise varying amounts of therapeutic agent.

375. The depot of any one of the preceding clauses, wherein the beads ormicrospheres comprise varying thicknesses of their respective controlregions.

376. The depot of any one of the preceding clauses, wherein the beads ofmicrospheres have varying dimensions.

377. The depot of any one of the preceding clauses, wherein the depotcomprises one of a plurality of pellets.

378. The depot of any one of the preceding clauses, wherein the pelletshave varying release profiles.

379. The depot of any one of the preceding clauses, wherein the pelletscomprise varying amounts of therapeutic agent.

380. The depot of any one of the preceding clauses, wherein the pelletscomprise varying thicknesses of their respective control regions.

381. The depot of any one of the preceding clauses, wherein the pelletshave varying dimensions.

382. The depot of any one of the preceding clauses, wherein the pelletsare substantially cylindrical.

383. The depot of any one of the preceding clauses, wherein the depotcomprises a plurality of substantially cylindrical beads, eachcomprising a therapeutic region and control region and wherein theplurality of beads are substantially aligned along a common longitudinalaxis.

384. The depot of any one of the preceding clauses, wherein the depot isbiodegradable and/or bioerodible.

385. The depot of any one of the preceding clauses, wherein the depot isa flexible solid that is structurally capable of being handled by aclinician during the normal course of a surgery without breaking intomultiple pieces and/or losing its general shape.

386. The depot of any one of the preceding clauses, wherein the depot isconfigured to be subcutaneously placed within a patient and release thetherapeutic agent in vivo for up to 7 days without breaking intomultiple pieces.

387. The depot of any one of the preceding clauses, wherein the depothas a surface area and a volume, and wherein a ratio of the surface areato volume is at least 1.

388. The depot of any one of the preceding clauses, wherein thediffusion openings include at least one or more pores and/or one or morechannels.

389. The depot of any one of the preceding clauses, wherein dissolutionof the releasing agent following in vivo placement in the treatment sitecauses the control region and the therapeutic region to transition froma state of lesser porosity to a state of greater porosity to facilitatethe release of the therapeutic agent from the depot.

390. The depot of any one of the preceding clauses, wherein thereleasing agent is a first releasing agent and the therapeutic regionincludes a second releasing agent mixed with the therapeutic agent.

391. The depot of any one of the preceding clauses, wherein thereleasing agent is a first releasing agent and the polymer is a firstpolymer, and the therapeutic region includes a second releasing agentand a second polymer mixed with the therapeutic agent.

392. The depot of any one of the preceding clauses, wherein the firstreleasing agent is the same as the second releasing agent.

393. The depot of any one of the preceding clauses, wherein the firstreleasing agent is the different than the second releasing agent.

394. The depot of any one of the preceding clauses, wherein aconcentration of the first releasing agent within the control region isthe greater than a concentration of the second releasing agent withinthe therapeutic region.

395. The depot of any one of the preceding clauses, wherein aconcentration of the first releasing agent within the control region isthe less than a concentration of the second releasing agent within thetherapeutic region.

396. The depot of any one of the preceding clauses, wherein aconcentration of the first releasing agent within the control region isthe same as a concentration of the second releasing agent within thetherapeutic region.

397. The depot of any one of the preceding clauses, wherein aconcentration of the first releasing agent within the control region isdifferent than a concentration of the second releasing agent within thetherapeutic region.

398. The depot of any one of the preceding clauses, wherein thetherapeutic region includes a plurality of microlayers.

399. The depot of any one of the preceding clauses, wherein the mass ofthe therapeutic agent comprises at least 50% of the mass of the depot.

400. The depot of any one of the preceding clauses, wherein the ratio ofthe mass of the therapeutic agent in the depot to the depot polymer massis at least at least 1:1, at least 2:1, 3:1, at least 4:1, at least 5:1,at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1,or at least 16:1.

401. The depot of any one of the preceding clauses, wherein thetherapeutic region comprises a bioresorbable polymer and the therapeuticagent.

402. The depot of any one of the preceding clauses, wherein thetherapeutic region includes at least 40% by weight of the therapeuticagent, at least 50% by weight of the therapeutic agent, at least 60% byweight of the therapeutic agent, 60% by weight of therapeutic agent, atleast 70% by weight of the therapeutic agent, at least 80% by weight ofthe therapeutic agent, at least 90% by weight of the therapeutic agent,or 100% by weight of the therapeutic agent.

403. The depot of any one of the preceding clauses, wherein the depotincludes at least 15% by weight of the therapeutic agent, at least 20%by weight of the therapeutic agent, at least 30% by weight of thetherapeutic agent, at least 40% by weight of the therapeutic agent, atleast 50% by weight of the therapeutic agent, at least 60% by weight ofthe therapeutic agent, at least 70% by weight of the therapeutic agent,at least 80% by weight of the therapeutic agent, at least 90% by weightof the therapeutic agent, 99% by weight of the therapeutic agent, or99.99% by weight of the therapeutic agent.

404. The depot of any one of the preceding clauses, wherein thereleasing agent is a non-ionic surfactant.

405. The depot of any one of the preceding clauses, wherein thereleasing agent has hydrophilic properties.

406. The depot of any one of the preceding clauses, wherein thereleasing agent is a polysorbate.

407. The depot of any one of the preceding clauses, wherein thereleasing agent is Tween 20.

408. The depot of any one of the preceding clauses, wherein thereleasing agent is Tween 80.

409. The depot of any one of the preceding clauses, wherein thereleasing agent is non-polymeric.

410. The depot of any one of the preceding clauses, wherein thereleasing agent is not a plasticizer.

411. The depot of any one of the preceding clauses, wherein the polymeris configured to degrade only after substantially all of the therapeuticagent has been released from the depot.

412. The depot of any one of the preceding clauses, wherein the polymeris a copolymer.

413. The depot of any one of the preceding clauses, wherein the polymeris a terpolymer.

414. The depot of any one of the preceding clauses, wherein the polymerincludes at least one of polyglycolide (PGA), polycaprolactone (PCL),poly(DL-lactic acid) (PLA), poly(alpha-hydroxy acids),poly(lactide-co-glycolide)(PLGA or DLG),poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate)(PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), polyphosphate ester),poly(amino acid), polydepsipeptides, poly(butylene succinate) (PBS),polyethylene oxide, polypropylene fumarate, polyiminocarbonates,poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone)(PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid,poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide),poly(D,L-lactide-co-glycolide), poly(gycolide-trimethylene carbonate),poly(ethyl glutamate-co-glutamic acid),poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate),tyrosine-derived polycarbonate, poly 1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinatepolyphosphazene, polycaprolactone co-butylacrylate, a copolymer ofpolyhydroxybutyrate, a copolymer of maleic anhydride, a copolymer ofpoly(trimethylene carbonate), polyethylene glycol (PEG),hydroxypropylmethylcellulose and cellulose derivatives, polysaccharides(such as hyaluronic acid, chitosan and starch), proteins (such asgelatin and collagen) or PEG derivatives, polyaspirins,polyphosphagenes, pre-gelatinized starch, hyaluronic acid, chitosans,gelatin, alginates, albumin, fibrin, vitamin E analogs, such as alphatocopheryl acetate, d-alpha tocopheryl succinate, D-lactide,D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL),D,L-lactide-glycolide-caprolactone (DL-G-CL), dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), methacrylates, poly(N-isopropylacrylamide),PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG,PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucroseacetate isobutyrate)hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose orsalts thereof, Carbopol®, poly(hydroxyethylmethacrylate),poly(methoxyethylmethacrylate), poly(methoxyethoxy-ethylmethacrylate),polymethylmethacrylate (PMMA), polyvinyl alcohols, propylene glycol, andpoly(DL-lactide-co-glycolide-co-caprolactone).

415. The depot of any one of the preceding clauses, wherein the polymeris one of poly(DL-lactide-co-glycolide-co-caprolactone) andpoly(DL-lactide-co-glycolide)(PLGA).

416. The depot of any one of the preceding clauses, wherein the polymeris poly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio ofabout 60:30:10.

417. The depot of any one of the preceding clauses, wherein the polymeris poly(DL-lactide-co-glycolide)(PLGA) in a molar ratio of between about10:90 and about 90:10.

418. The depot of any one of the preceding clauses, wherein the polymeris poly(DL-lactide-co-glycolide)(PLGA) in a molar ratio of about 50:50.

419. The depot of any one of the preceding clauses, wherein the polymeris ester-terminated.

420. The depot of any one of the preceding clauses, wherein the polymeris a terpolymer that includes three polymers selected from thefollowing: polyglycolide (PGA), polycaprolactone (PCL), poly(L-lacticacid) (PLA), poly(DL-lactic acid) (PLA), poly(trimethylene carbonate)(PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), and polyethylene glycol.

421. The depot of any one of the preceding clauses, wherein the polymeris a first polymer, and the therapeutic region includes a second polymermixed with the therapeutic agent.

422. The depot of any one of the preceding clauses, wherein the firstpolymer and/or the second polymer include at least one of polyglycolide(PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA),poly(alpha-hydroxy acids), poly(lactide-co-glycolide)(PLGA or DLG),poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate)(PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), polyphosphate ester),poly(amino acid), polydepsipeptides, poly(butylene succinate) (PBS),polyethylene oxide, polypropylene fumarate, polyiminocarbonates,poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone)(PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid,poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide),poly(D,L-lactide-co-glycolide), poly(gycolide-trimethylene carbonate),poly(ethyl glutamate-co-glutamic acid),poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate),tyrosine-derived polycarbonate, poly 1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinatepolyphosphazene, polycaprolactone co-butylacrylate, a copolymer ofpolyhydroxybutyrate, a copolymer of maleic anhydride, a copolymer ofpoly(trimethylene carbonate), polyethylene glycol (PEG),hydroxypropylmethylcellulose and cellulose derivatives, polysaccharides(such as hyaluronic acid, chitosan and starch), proteins (such asgelatin and collagen) or PEG derivatives, polyaspirins,polyphosphagenes, pre-gelatinized starch, hyaluronic acid, chitosans,gelatin, alginates, albumin, fibrin, vitamin E analogs, such as alphatocopheryl acetate, d-alpha tocopheryl succinate, D-lactide,D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL),D,L-lactide-glycolide-caprolactone (DL-G-CL), dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), methacrylates, poly(N-isopropylacrylamide),PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG,PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAM (sucroseacetate isobutyrate)hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose orsalts thereof, Carbopol®, poly(hydroxyethylmethacrylate),poly(methoxyethylmethacrylate), poly(methoxyethoxy-ethylmethacrylate),polymethylmethacrylate (PMMA), polyvinyl alcohols, propylene glycol,poly(DL-lactide-co-glycolide-co-caprolactone).

423. The depot of any one of the preceding clauses, wherein the firstpolymer and/or the second polymer selected from the following:poly(DL-lactide-co-glycolide-co-caprolactone) andpoly(DL-lactide-co-glycolide)(PLGA).

424. The depot of any one of the preceding clauses, wherein the firstpolymer and/or the second polymer ispoly(DL-lactide-co-glycolide-co-caprolactone) and has a molar ratio ofabout 60:30:10.

425. The depot of any one of the preceding clauses, wherein the firstpolymer and/or the second polymer is poly(DL-lactide-co-glycolide) andhas a molar ratio of about 50:50.

426. The depot of any one of the preceding clauses, wherein the firstpolymer and/or the second polymer is ester-terminated.

427. The depot of any one of the preceding clauses, wherein the firstpolymer and/or the second polymer is a terpolymer that includes threepolymers selected from the following: polyglycolide (PGA),polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(trimethylenecarbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), and polyethylene glycol.

428. The depot of any one of the preceding clauses, wherein the ratio ofthe polymer to the releasing agent in the control region is at least1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, or atleast 15:1

429. The depot of any one of the preceding clauses, wherein thereleasing agent is configured to dissolve when the depot is placed incontact with phosphate buffered saline to form diffusion openings.

430. A system for delivering a therapeutic agent to a treatment site,the system comprising:

-   -   a shaft having a lumen;    -   a pusher operatively coupled to the lumen; and    -   a depot disposed within the lumen and configured to be displaced        from the shaft via activation of the pusher, the depot        comprising:        -   a therapeutic region comprising the therapeutic agent, the            therapeutic region elongated along a first axis;        -   a control region at least partially surrounding the            therapeutic region and elongated along the first axis, the            control region comprising a bioresorbable polymer and a            releasing agent mixed with the polymer, wherein the            releasing agent is configured to dissolve when the depot is            placed in vivo to form diffusion openings in the control            region; and        -   wherein the depot is configured to be implanted at a            treatment site in vivo and, while implanted, release the            therapeutic agent at the treatment site for a period of time            not less than 3 days.

431. The system of clause 430, wherein the depot comprises the depot ofany one of the preceding clauses.

432. The system of clause 430, wherein the shaft comprises a needle, andwherein the pusher comprises a plunger.

433. A system for delivering a therapeutic agent to a treatment site,the system comprising:

-   -   an expandable member configured to be expanded from a        reduced-volume configuration for delivery to an expanded-volume        configuration for deployment at the treatment site; and    -   a depot carried by the expandable member, the depot comprising:        -   a therapeutic region comprising the therapeutic agent, the            therapeutic region elongated along a first axis;        -   a control region at least partially surrounding the            therapeutic region and elongated along the first axis, the            control region comprising a bioresorbable polymer and a            releasing agent mixed with the polymer, wherein the            releasing agent is configured to dissolve when the depot is            placed in vivo to form diffusion openings in the control            region; and        -   wherein the depot is configured to be implanted at a            treatment site in vivo and, while implanted, release the            therapeutic agent at the treatment site for a period of time            not less than 3 days.

434. The system of clause 433, wherein the depot comprises the depot ofany one of the preceding clauses.

435. The system of any one of the preceding clauses, wherein theexpandable member comprises a stent.

436. The system of any one of the preceding clauses, wherein theexpandable member comprises a spherical, semi-spherical, ellipsoid, orsemi-ellipsoid structure.

437. The system of any one of the preceding clauses, wherein theexpandable member comprises a curved outer surface, and wherein thedepot is disposed over the curved outer surface.

438. The system of any one of the preceding clauses, wherein the depotsubstantially covers at least one surface of the expandable member.

439. The system of any one of the preceding clauses, wherein theexpandable member comprises a shape-memory material.

440. The system of any one of the preceding clauses, wherein the depotis disposed in a lubricious coating and wherein the lubricious coatingcomprises a hydrogel.

441. A method for delivering a therapeutic agent to a treatment sitewithin a body:

-   -   positioning a depot at a treatment site in vivo having        physiologic fluids, the depot comprising:        -   a therapeutic region comprising the therapeutic agent, the            therapeutic region elongated along a first axis;        -   a control region at least partially surrounding the            therapeutic region and elongated along the first axis, the            control region comprising a bioresorbable polymer and a            releasing agent mixed with the polymer; and    -   allowing the releasing agent to dissolve at the treatment site        to form diffusion openings in the control region, thereby        releasing the therapeutic agent from the depot to the treatment        site for a period of time not less than 3 days.

442. The method of clause 441, wherein the depot comprises the depot ofany one of the preceding clauses.

443. The method of any one of the preceding clauses, wherein positioningthe depot comprises inserting the depot subcutaneously at the treatmentsite via a needle.

444. The method of any one of the preceding clauses, wherein positioningthe depot comprises positioning the depot proximate to a nerve bundle atthe treatment site.

445. The method of any one of the preceding clauses, further comprisingdissolving the releasing agent at a first rate and degrading the polymerat a second rate, wherein the first rate is greater than the secondrate.

446. The method of any one of the preceding clauses, further comprisingdissolving the releasing agent in response to contact between thecontrol region and the physiologic fluids at the treatment site.

447. The method of any one of the preceding clauses, further comprisingcreating diffusion openings in the control region via the dissolution ofthe releasing agent in response to physiologic fluids at the treatmentsite.

448. The method of any one of the preceding clauses, wherein thereleasing agent is a first releasing agent and the therapeutic regionincludes a second releasing agent, and wherein the method furthercomprises creating microchannels in the therapeutic region and thecontrol region via dissolution of the first and/or second releasingagents.

449. The method of any one of the preceding clauses, wherein at leastsome of the microchannels penetrate both the therapeutic region and thecontrol region.

450. The method of any one of the preceding clauses, further includingincreasing a porosity of the depot via dissolution of the releasingagent.

451. The method of any one of the preceding clauses, wherein thetherapeutic agent is released one or more times in substantiallydiscrete doses after implantation.

452. The method of any one of the preceding clauses, wherein thetherapeutic agent is released at a substantially steady state rate forthe period of time.

453. The method of any one of the preceding clauses, wherein the periodof time is not less than 8 days, no less than 9 days, no less than 10days, no less than 11 days, no less than 12 days, no less than 13 days,no less than 14 days, no less than 15 days, no less than 16 days, noless than 17 days, no less than 18 days, no less than 19 days, no lessthan 20 days, no less than 21 days, no less than 22 days, no less than23 days, no less than 24 days, no less than 25 days, no less than 26days, no less than 27 days, no less than 28 days, no less than 29 days,no less than 30 days, no less than 40 days, no less than 50 days, noless than 60 days, no less than 70 days, no less than 90 days, no lessthan 100 days, no less than 200 days, no less than 300 days, or no lessthan 365 days.

454. The method of any one of the preceding clauses, wherein the depotis a first depot and the method further comprises positioning a seconddepot at the treatment site.

455. A depot for implantation in a mammalian patient for the sustained,controlled release of a therapeutic agent, the depot comprising:

-   -   a therapeutic region comprising the therapeutic agent;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region; and    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the therapeutic agent        at the treatment site for no less than 3 days.

456. The depot of clause 455, wherein the therapeutic agent in thetherapeutic region comprises at least 50% of the total weight of thedepot.

457. The depot of any one of the preceding clauses, wherein the depot isconfigured to release the therapeutic agent at a first rate for a firstperiod of time and at a second rate for a second period of time.

458. The depot of clause 457, wherein the first rate is greater than thesecond rate.

459. The depot of clause 457, wherein the first period of time isgreater than the second period of time.

460. The depot of clause 457, wherein the first period of time is lessthan the second period of time.

461. The depot of any one of the preceding clauses, wherein the depot isconfigured to release the therapeutic agent at the treatment site invivo for no less than 4 days, no less than 5 days, no less than 6 days,no less than 7 days, no less than 8 days, no less than 9 days, no lessthan 10 days, no less than 11 days, no less than 12 days, no less than13 days, no less than 14 days, no less than 15 days, no less than 16days, no less than 17 days, no less than 18 days, no less than 19 days,no less than 20 days, no less than 21 days, no less than 22 days, noless than 23 days, no less than 24 days, no less than 25 days, no lessthan 26 days, no less than 27 days, no less than 28 days, no less than29 days, no less than 30 days, no less than 40 days, no less than 50days, no less than 60 days, no less than 70 days, no less than 90 days,no less than 100 days, no less than 200 days, no less than 300 days, orno less than 365 days.

462. The depot of any one of the preceding clauses, wherein thetherapeutic region comprises a covered portion and an exposed portion,wherein the covered portion is covered by the control region such that,when the depot is initially positioned at the treatment site in vivo,the control region is between the covered portion of the therapeuticregion and physiologic fluids at the treatment site and the exposedportion of the therapeutic region is exposed to the physiologic fluids.

463. The depot of any one of the preceding clauses, wherein,

-   -   the depot has a total surface area comprising the exposed        surface area of the control region plus the exposed surface area        of the therapeutic region, and    -   when the depot is initially positioned at the treatment site in        vivo, a ratio of the exposed surface area of the therapeutic        region to the exposed surface area of the control region is from        about 5% to about 20%, or from about 5% to about 15%, or from        about 5% to about 10%.

464. The depot of clause 463, wherein the exposed surface area of thecontrol region is less than the exposed surface area of the therapeuticregion.

465. The depot of clause 463, wherein the exposed surface area of thecontrol region is greater than the exposed surface area of thetherapeutic region.

466. The depot of any one of the preceding clauses, wherein the controlregion is a first control region, and wherein the depot comprises asecond control region.

467. The depot of clause 466, wherein the first control region isdisposed at a first side of the therapeutic region and the secondcontrol region is disposed at a second side of the therapeutic regionopposite the first side.

468. The depot of any one of the preceding clauses, wherein the depotcomprises a plurality of control regions and a plurality of therapeuticregions, and wherein each of the therapeutic regions is separated froman adjacent one of the therapeutic regions by one or more controlregions.

469. The depot of clause 468, wherein each of the therapeutic regionsand each of the control regions has a thickness less than 1 mm.

470. The depot of clause 468 or clause 469, wherein the depot comprisesfrom about 2 to about 4 therapeutic regions.

471. The depot of clause 468 or clause 469, wherein the depot comprisesfrom about 2 to about 10 control regions.

472. The depot of any one of clauses 1 to 461, wherein the therapeuticregion is enclosed by the control region such that, when the depot ispositioned at the treatment site in vivo, the control region is betweenthe therapeutic region and physiologic fluids at the treatment site.

473. The depot of any one of the preceding clauses, wherein the controlregion comprises a first control layer and a second control layer.

474. The depot of clause 473, wherein the second control layer isadjacent to the therapeutic region and the first control layerencapsulates/encloses the therapeutic region and the second controllayer.

475. The depot of clause 473 or clause 474, wherein the first controllayer and the second control layer together enclose the therapeuticregion.

476. The depot of any one of clauses 473 to 475, wherein the firstcontrol layer is disposed at a first side of the therapeutic region andthe second control layer is disposed at a second side of the therapeuticregion opposite the first side.

477. The depot of any one of clauses 473 to 476, wherein the firstcontrol layer comprises a first plurality of sub-layers and the secondcontrol layer comprises a second plurality of sub-layers.

478. The depot of any one of clauses 473 to 477, wherein the firstcontrol layer includes a first amount of the releasing agent and thesecond control layer includes a second amount of the releasing agentdifferent than the first amount.

479. The depot of any one of clauses 473 to 478, wherein the secondcontrol layer is positioned between the first control layer and thetherapeutic region, and wherein the first control layer includes a firstconcentration of the releasing agent and the second control layerincludes a second concentration of the releasing agent greater than thefirst concentration.

480. The depot of any one of clauses 473 to 479, wherein the secondcontrol layer is positioned between the first control layer and thetherapeutic region, and wherein the first control layer includes a firstconcentration of the releasing agent and the second control layerincludes a second concentration of the releasing agent less than thefirst concentration.

481. The depot of any one of clauses 473 to 480, wherein the secondcontrol layer is positioned between the first control layer and thetherapeutic region, and wherein

-   -   the first control layer includes up to 5% by weight of the        releasing agent, up to 10% by weight of the releasing agent, up        to 15% by weight of the releasing agent, up to 20% by weight of        the releasing agent, up to 25% by weight of the releasing agent,        up to 30% by weight of the releasing agent, up to 35% by weight        of the releasing agent, up to 40% by weight of the releasing        agent, up to 45% by weight of the releasing agent, or 50% by        weight of the releasing agent, and    -   the second control layer includes up to 5% by weight of the        releasing agent, up to 10% by weight of the releasing agent, up        to 15% by weight of the releasing agent, up to 20% by weight of        the releasing agent, up to 25% by weight of the releasing agent,        up to 30% by weight of the releasing agent, up to 35% by weight        of the releasing agent, up to 40% by weight of the releasing        agent, up to 45% by weight of the releasing agent, or up to 50%        by weight of the releasing agent.

482. The depot of any one of clauses 473 to 481, wherein the secondcontrol layer is positioned between the first control layer and thetherapeutic region, and wherein the first control layer includes a firstamount of the releasing agent and the second control layer includes asecond amount of the releasing agent, the second amount being at least2×, at least 3×, at least 4×, or at least 5× the first amount.

483. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/10 of a thickness ofthe therapeutic region.

484. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/12.5 of a thickness ofthe therapeutic region.

485. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/15 of a thickness ofthe therapeutic region.

486. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/17.5 of a thickness ofthe therapeutic region.

487. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/20 of a thickness ofthe therapeutic region.

488. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/22.5 of a thickness ofthe therapeutic region.

489. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/25 of a thickness ofthe therapeutic region.

490. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/30 of a thickness ofthe therapeutic region.

491. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/40 of a thickness ofthe therapeutic region.

492. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/50 of a thickness ofthe therapeutic region.

493. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/75 of a thickness ofthe therapeutic region.

494. The depot of any one of the preceding clauses, wherein a thicknessof the control region is less than or equal to 1/100 of a thickness ofthe therapeutic region.

495. The depot of any one of the preceding clauses, wherein the depot isa flexible solid that is structurally capable of being handled by aclinician during the normal course of a surgery without breaking intomultiple pieces and/or losing its general shape.

496. The depot of any one of the preceding clauses, wherein the depot isconfigured to be placed in the knee of a patient and release thetherapeutic agent in vivo for up to 7 days without breaking intomultiple pieces.

497. The depot of any one of the preceding clauses, wherein the depothas a width and a thickness, and wherein a ratio of the width to thethickness is 21 or greater.

498. The depot of clause 65, wherein the ratio is 30 or greater.

499. The depot of clause 65, wherein the ratio is 40 or greater.

500. The depot of any one of the preceding clauses, wherein the depothas a surface area and a volume, and wherein a ratio of the surface areato volume is at least 1.

501. The depot of any one of the preceding clauses, wherein thediffusion openings include at least one or more pores and/or one or morechannels.

502. The depot of any one of the preceding clauses, wherein the two ormore micro-thin layers of the bioresorbable polymer are bonded via heatcompression to form the therapeutic region.

503. The depot of any one of the preceding clauses, wherein the controlregion and the therapeutic region are bonded via heat compression.

504. The depot of any one of the preceding clauses, wherein the controlregion and the therapeutic region are thermally bonded.

505. The depot of any one of the preceding clauses, wherein dissolutionof the releasing agent following in vivo placement in the treatment sitecauses the control region and the therapeutic region to transition froma state of lesser porosity to a state of greater porosity to facilitatethe release of the therapeutic agent from the depot.

506. The depot of any one of the preceding clauses, wherein the controlregion does not include the therapeutic agent at least prior toimplantation of the depot at the treatment site.

507. The depot of any one of clauses 1 to 505, wherein the controlregion comprises a therapeutic agent different from the therapeuticagent in the therapeutic region.

508. The depot of any one of the preceding clauses, wherein thetherapeutic region does not include any releasing agent prior toimplantation of the depot at the treatment site.

509. The depot of any one of the preceding clauses, wherein thereleasing agent is a first releasing agent and the therapeutic regionincludes a second releasing agent mixed with the therapeutic agent.

510. The depot of any one of clauses 1 to 509, wherein the releasingagent is a first releasing agent and the polymer is a first polymer, andthe therapeutic region includes a second releasing agent and a secondpolymer mixed with the therapeutic agent.

511. The depot of any one of clauses 1 to 509, wherein the firstreleasing agent is the same as the second releasing agent.

512. The depot of any one of clauses 1 to 509, wherein the firstreleasing agent is the different than the second releasing agent.

513. The depot of any one of clauses 1 to 512, wherein a concentrationof the first releasing agent within the control region is the greaterthan a concentration of the second releasing agent within thetherapeutic region.

514. The depot of any one of clauses 1 to 512, wherein a concentrationof the first releasing agent within the control region is the less thana concentration of the second releasing agent within the therapeuticregion.

515. The depot of any one of clauses 1 to 512, wherein a concentrationof the first releasing agent within the control region is the same as aconcentration of the second releasing agent within the therapeuticregion.

516. The depot of any one of clauses 1 to 512, wherein a concentrationof the first releasing agent within the control region is different thana concentration of the second releasing agent within the therapeuticregion.

517. The depot of any one of clauses 1 to 516, wherein the firstreleasing agent is different than the second releasing agent.

518. The depot of any one of the preceding clauses, wherein thetherapeutic region includes a plurality of microlayers.

519. The depot of any one of the preceding clauses, wherein the mass ofthe therapeutic agent comprises at least 50% of the mass of the depot.

520. The depot of any one of the preceding clauses, wherein the ratio ofthe mass of the therapeutic agent in the depot to the depot polymer massis at least 3:1.

521. The depot of any one of the preceding clauses, wherein the ratio ofthe mass of the therapeutic agent in the depot to the depot polymer massis at least 4:1.

522. The depot of any one of the preceding clauses, wherein the ratio ofthe mass of the therapeutic agent in the depot to the depot polymer massis at least 5:1.

523. The depot of any one of the preceding clauses, wherein a ratio ofthe mass of the therapeutic agent in the depot to the depot polymer massis at least 6:1.

524. The depot of any one of the preceding clauses, wherein a ratio ofthe mass of the therapeutic agent in the depot to the depot polymer massis at least 7:1.

525. The depot of any one of the preceding clauses, wherein a ratio ofthe mass of the therapeutic agent in the depot to the depot polymer massis at least 8:1.

526. The depot of any one of the preceding clauses, wherein a ratio ofthe mass of the therapeutic agent in the depot to the depot polymer massis at least 10:1.

527. The depot of any one of the preceding clauses, wherein a ratio ofthe mass of the therapeutic agent in the depot to the depot polymer massis at least 16:1.

528. The depot of any one of the preceding clauses, wherein thetherapeutic region includes at least 60% by weight of the therapeuticagent, 60% by weight of the therapeutic agent, at least 70% by weight ofthe therapeutic agent, at least 80% by weight of the therapeutic agent,at least 90% by weight of the therapeutic agent, or 100% by weight ofthe therapeutic agent.

529. The depot of any one of the preceding clauses, wherein the depotincludes at least 15% by weight of the therapeutic agent, at least 20%by weight of the therapeutic agent, at least 30% by weight of thetherapeutic agent, at least 40% by weight of the therapeutic agent, atleast 50% by weight of the therapeutic agent, at least 60% by weight ofthe therapeutic agent, at least 70% by weight of the therapeutic agent,at least 80% by weight of the therapeutic agent, at least 90% by weightof the therapeutic agent, or 100% by weight of the therapeutic agent.

530. The depot of any one of the preceding clauses, wherein thetherapeutic agent comprises at least one of: simple analgesics, localanesthetics, NSAIDs and opioids.

531. The depot of any one of the preceding clauses, wherein thetherapeutic agent comprises a local anesthetic selected from at leastone of bupivacaine, ropivacaine, mepivacaine, and lidocaine.

532. The depot of any one of the preceding clauses, further comprisingan antibiotic, an antifungal, and/or an antimicrobial, wherein theantibiotic, the antifungal, and/or the antimicrobial is selected from atleast one of amoxicillin, amoxicillin/clavulanate, cephalexin,ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin,sulfamethoxazole/trimethoprim, tetracycline(s), minocycline,tigecycline, doxycycline, rifampin, triclosan, chlorhexidine,penicillin(s), aminoglycides, quinolones, fluoroquinolones, vancomycin,gentamycin, cephalosporin(s), carbapenems, imipenem, ertapenem,antimicrobial peptides, cecropin-mellitin, magainin, dermaseptin,cathelicidin, α-defensins, and α-protegrins, ketoconazole,clortrimazole, miconazole, econazole, intraconazole, fluconazole,bifoconazole, terconazole, butaconazole, tioconazole, oxiconazole,sulconazole, saperconazole, voriconazole, terbinafine, amorolfine,naftifine, griseofulvin, haloprogin, butenafine, tolnaftate, nystatin,cyclohexamide, ciclopirox, flucytosine, terbinafine, and amphotericin B.

533. The depot of any one of the preceding clauses, further comprisingan anti-inflammatory agent selected from at least one of steroids,prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone andmethylprednisolone, non-steroidal anti-inflammatory drugs (NSAIDs),aspirin, Ibuprofen, naproxen sodium, diclofenac, diclofenac-misoprostol,celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac,diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac,fenoprofen, flurbiprofen, ketorolac, meclofenamate, mefenamic acid, andCOX-2 inhibitors.

534. The depot of any one of the preceding clauses, wherein thetherapeutic agent is dexamethasone.

535. The depot of any one of the preceding clauses, further comprisingat least one of: epinephrine, clonidine, transexamic acid.

536. The depot of any one of the preceding clauses, wherein thereleasing agent is a non-ionic surfactant.

537. The depot of any one of the preceding clauses, wherein thereleasing agent has hydrophilic properties.

538. The depot of any one of the preceding clauses, wherein thereleasing agent is a polysorbate.

539. The depot of any one of the preceding clauses, wherein thereleasing agent is Tween 20.

540. The depot of any one of clauses 1 to 107, wherein the releasingagent is Tween 80.

541. The depot of any one of the preceding clauses, wherein thereleasing agent is non-polymeric.

542. The depot of any one of the preceding clauses, wherein thereleasing agent is not a plasticizer.

543. The depot of any one of the preceding clauses, wherein the polymeris configured to degrade only after substantially all of the therapeuticagent has been released from the depot.

544. The depot of any one of the preceding clauses, wherein the polymeris a copolymer.

545. The depot of any one of clauses 1 to 545, wherein the polymer is aterpolymer.

546. The depot of any one of the preceding clauses, wherein the polymerincludes at least one of polyglycolide (PGA), polycaprolactone (PCL),poly(DL-lactic acid) (PLA), poly(alpha-hydroxy acids),poly(lactide-co-glycolide)(PLGA or DLG),poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate)(PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), polyphosphate ester),poly(amino acid), polydepsipeptides, poly(butylene succinate) (PBS),polyethylene oxide, polypropylene fumarate, polyiminocarbonates,poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone)(PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid,poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide),poly(D,L-lactide-co-glycolide), poly(gycolide-trimethylene carbonate),poly(ethyl glutamate-co-glutamic acid),poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate),tyrosine-derived polycarbonate, poly 1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinatepolyphosphazene, polycaprolactone co-butylacrylate, a copolymer ofpolyhydroxybutyrate, a copolymer of maleic anhydride, a copolymer ofpoly(trimethylene carbonate), polyethylene glycol (PEG),hydroxypropylmethylcellulose and cellulose derivatives, polysaccharides(such as hyaluronic acid, chitosan and starch), proteins (such asgelatin and collagen) or PEG derivatives, polyaspirins,polyphosphagenes, collagen, starch, pre-gelatinized starch, hyaluronicacid, chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs,such as alpha tocopheryl acetate, d-alpha tocopheryl succinate,D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL),D,L-lactide-glycolide-caprolactone (DL-G-CL), dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), methacrylates, poly(N-isopropylacrylamide),PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG,PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucroseacetate isobutyrate)hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose orsalts thereof, Carbopol®, poly(hydroxyethylmethacrylate),poly(methoxyethylmethacrylate), poly(methoxyethoxy-ethylmethacrylate),polymethylmethacrylate (PMMA), methylmethacrylate (AMA), gelatin,polyvinyl alcohols, propylene glycol, andpoly(DL-lactide-co-glycolide-co-caprolactone).

547. The depot of any one of the preceding clauses, wherein the polymeris one of poly(DL-lactide-co-glycolide-co-caprolactone) andpoly(DL-lactide-co-glycolide)(PLGA).

548. The depot of any one of clauses 1 to 545, wherein the polymer ispoly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio of60:30:10.

549. The depot of any one of clauses 1 to 545, wherein the polymer ispoly(DL-lactide-co-glycolide)(PLGA) in a molar ratio of 50:50.

550. The depot of any one of the preceding clauses, wherein the polymeris ester-terminated.

551. The depot of any one of the preceding clauses, wherein the polymeris a terpolymer that includes three polymers selected from thefollowing: polyglycolide (PGA), polycaprolactone (PCL), poly(L-lacticacid) (PLA), poly(DL-lactic acid) (PLA), poly(trimethylene carbonate)(PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), and polyethylene glycol.

552. The depot of any one of the preceding clauses, wherein the polymeris a first polymer, and the therapeutic region includes a second polymermixed with the therapeutic agent.

553. The depot of clause 552, wherein the first polymer and the secondpolymer are the same.

554. The depot of clause 552, wherein the first polymer and the secondpolymer are different.

555. The depot of any one of clauses 552 to 554, wherein the firstpolymer and/or the second polymer include at least one of polyglycolide(PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA),poly(alpha-hydroxy acids), poly(lactide-co-glycolide)(PLGA or DLG),poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate)(PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), polyphosphate ester),poly(amino acid), polydepsipeptides, poly(butylene succinate) (PBS),polyethylene oxide, polypropylene fumarate, polyiminocarbonates,poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone)(PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid,poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide),poly(D,L-lactide-co-glycolide), poly(gycolide-trimethylene carbonate),poly(ethyl glutamate-co-glutamic acid),poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate),tyrosine-derived polycarbonate, poly 1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinatepolyphosphazene, polycaprolactone co-butylacrylate, a copolymer ofpolyhydroxybutyrate, a copolymer of maleic anhydride, a copolymer ofpoly(trimethylene carbonate), polyethylene glycol (PEG),hydroxypropylmethylcellulose and cellulose derivatives, polysaccharides(such as hyaluronic acid, chitosan and starch), proteins (such asgelatin and collagen) or PEG derivatives, polyaspirins,polyphosphagenes, collagen, starch, pre-gelatinized starch, hyaluronicacid, chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs,such as alpha tocopheryl acetate, d-alpha tocopheryl succinate,D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL),D,L-lactide-glycolide-caprolactone (DL-G-CL), dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), methacrylates, poly(N-isopropylacrylamide),PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG,PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAM (sucroseacetate isobutyrate)hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose orsalts thereof, Carbopol®, poly(hydroxyethylmethacrylate),poly(methoxyethylmethacrylate), poly(methoxyethoxy-ethylmethacrylate),polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol,poly(DL-lactide-co-glycolide-co-caprolactone).

556. The depot of any one of clauses 552 to 554, wherein the firstpolymer and/or the second polymer is selected from the following:poly(DL-lactide-co-glycolide-co-caprolactone) andpoly(DL-lactide-co-glycolide)(PLGA).

557. The depot of any one of clauses 552 to 554, wherein the firstpolymer and/or the second polymer ispoly(DL-lactide-co-glycolide-co-caprolactone) and has a molar ratio of60:30:10.

558. The depot of any one of clauses 552 to 554, wherein the firstpolymer and/or the second polymer is poly(DL-lactide-co-glycolide) andhas a molar ratio of 50:50.

559. The depot of any one of the preceding clauses, wherein the firstpolymer and/or the second polymer is ester-terminated.

560. The depot of any one of the preceding clauses, wherein the firstpolymer and/or the second polymer is a terpolymer that includes threepolymers selected from the following: polyglycolide (PGA),polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(trimethylenecarbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), and polyethylene glycol.

561. The depot of any one of the preceding clauses, wherein the ratio ofthe releasing agent to the polymer in the control region is no more than1:2.

562. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is no more than1:3.

563. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is no more than1:4.

564. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is no more than1:5.

565. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is no more than1:6.

566. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is no more than1:7.

567. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is no more than1:8.

568. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is no more than1:9.

569. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is no more than1:10.

570. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is no more than1:11.

571. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is at least1:1.

572. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is at least2:1.

573. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is at least3:1.

574. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is at least4:1.

575. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is at least5:1.

576. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is at least6:1.

577. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is at least7:1.

578. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is at least8:1.

579. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is at least9:1.

580. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is at least10:1.

581. The depot of any one of clauses 455 to 560, wherein the ratio ofthe releasing agent to the polymer in the control region is at least15:1.

582. The depot of any one of the preceding clauses, wherein:

-   -   the polymer is a first polymer and the therapeutic region        further includes a second polymer,    -   the depot has a depot polymer mass equivalent to a mass of the        first polymer plus a mass of the second polymer, and    -   a ratio of a mass of the therapeutic agent in the depot to the        depot polymer mass is approximately 1:1.

583. The depot of clause 582, wherein the first polymer is the same asthe second polymer.

584. The depot of clause 582, wherein the first polymer is differentthan the second polymer.

585. The depot of any one of clauses 582 to 584, wherein the ratio ofthe mass of the therapeutic agent in the depot to the depot polymer massis at least 2:1.

586. The depot of any one of clauses 582 to 584, wherein the ratio ofthe mass of the therapeutic agent in the depot to the depot polymer massis at least 3:1.

587. The depot of any one of clauses 582 to 584, wherein the ratio ofthe mass of the therapeutic agent in the depot to the depot polymer massis at least 4:1.

588. The depot of any one of clauses 582 to 584, wherein the ratio ofthe mass of the therapeutic agent in the depot to the depot polymer massis approximately 5:1.

589. The depot of any one of clauses 582 to 584, wherein a ratio of themass of the therapeutic agent in the depot to the depot polymer mass isat least 6:1.

590. The depot of any one of clauses 582 to 584, wherein a ratio of themass of the therapeutic agent in the depot to the depot polymer mass isat least 7:1.

591. The depot of any one of clauses 582 to 584, wherein a ratio of themass of the therapeutic agent in the depot to the depot polymer mass isat least 8:1.

592. The depot of any one of clauses 582 to 584, wherein a ratio of themass of the therapeutic agent in the depot to the depot polymer mass isat least 10:1.

593. The depot of any one of clauses 582 to 584, wherein a ratio of themass of the therapeutic agent in the depot to the depot polymer mass isat least 16:1.

594. A method for treating a patient suffering from pain at ananatomical region of the patient's body, the pain associated with asurgery at or near the anatomical region, the method comprising:improving a Western Ontario and McMaster Universities Osteoarthritis(WOMAC) index total score of the patient by implanting one or more ofthe depots of the preceding clauses at a surgical site at the anatomicalregion.

595. A method for treating a patient suffering from pain at ananatomical region of the patient's body, the pain associated with asurgery at or near the anatomical region, the method comprising:improving a WOMAC index pain sub-score of the patient by implanting oneor more of the depots of the preceding clauses at a surgical site at theanatomical region.

596. A method for treating a patient suffering from pain at ananatomical region of the patient's body, the pain associated with asurgery at or near the anatomical region, the method comprising:improving a WOMAC index stiffness sub-score of the patient by implantingone or more of the depots of the preceding clauses at a surgical site atthe anatomical region.

597. A method for treating a patient suffering from pain at ananatomical region of the patient's body, the pain associated with asurgery at or near the anatomical region, the method comprising:improving a WOMAC index physical function sub-score of the patient byimplanting one or more of the depots of the preceding clauses at asurgical site at the anatomical region.

598. A method for treating a patient suffering from pain at ananatomical region of the patient's body, the pain associated with asurgery at or near the anatomical region, the method comprising:improving a KOOS score of the patient by implanting one or more of thedepots of the preceding clauses at a surgical site at the anatomicalregion.

599. A method for treating a patient suffering from pain at ananatomical region of the patient's body, the pain associated with asurgery at or near the anatomical region, the method comprisingimproving a range of motion at the anatomical region by relieving painat the anatomical region via implantation of any one of the depots ofthe preceding clauses.

600. A method for treating a patient suffering from pain at ananatomical region of the patient's body, the pain associated with asurgery at or near the anatomical region, the method comprising reducingan amount of opioids consumed by the patient.

601. A method of improving a WOMAC index total score in a patientsuffering from pain associated with a surgery at or near the anatomicalregion of the patient's body, the method comprising implanting a depotat a surgical site at or near the anatomical region, wherein the depotis any one of the depots of the preceding clauses.

602. The method of the preceding clause, wherein the WOMAC index totalscore comprises a pain sub-score, a stiffness sub-score, and/or aphysical function sub-score.

603. The method of any one of the preceding clauses, wherein the pain isassociated with an orthopedic surgery.

604. The method of any one of the preceding clauses, wherein the pain isassociated with a joint surgery.

605. The method of any one of the preceding clauses, wherein the pain isassociated with a total knee arthoplasty.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present disclosure can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present disclosure.

FIG. 1 depicts the release of a therapeutic agent over time from a priorart device.

FIG. 2 is an isometric view of a depot configured in accordance with thepresent technology.

FIG. 3 depicts the release profile over time of one or more depots ofthe present technology.

FIG. 4 is an isometric view of a depot in accordance with someembodiments of the present technology.

FIG. 5 is an isometric view of a depot in accordance with someembodiments of the present technology.

FIG. 6 is a cross-sectional view of a depot in accordance with someembodiments of the present technology.

FIG. 7 is a cross-sectional view of a depot in accordance with someembodiments of the present technology.

FIG. 8 is a cross-sectional view of a depot in accordance with someembodiments of the present technology.

FIG. 9A is an isometric view of a depot in accordance with someembodiments of the present technology.

FIG. 9B is a cross-sectional view of the depot shown in FIG. 9A.

FIG. 10 is a cross-sectional view of a depot in accordance with someembodiments of the present technology.

FIG. 11 is a cross-sectional view of a depot in accordance with someembodiments of the present technology.

FIG. 12 is a cross-sectional view of a depot in accordance with someembodiments of the present technology.

FIG. 13 is an isometric view of a depot in accordance with someembodiments of the present technology.

FIGS. 14A-H are depots having different cross-sectional areas and shapesin accordance with the present technology.

FIG. 15 depicts the maximum flexural load of an implant over time fromtesting performed on implant samples submerged in buffered solution.

FIGS. 16A-16E depict various depot embodiments including a barrierregion in accordance with the technology.

FIG. 17 is a schematic representation of core acidification of the priorart.

FIG. 18 is a scanning electron microscope image of a polymer tablet ofthe prior art after 20 days of degradation.

FIG. 19A is a schematic representation of the degradation of the depotsof the present technology.

FIGS. 19B and 19C are scanning electron microscope (“SEM”) images ofcross-sections of depots of the present technology at differenttimepoints during degradation.

FIG. 20 is a perspective view of a depot in accordance with someembodiments of the present technology.

FIG. 21 is cross-sectional view of a depot in accordance with someembodiments of the present technology.

FIG. 22 is cross-sectional view of a depot in accordance with someembodiments of the present technology.

FIG. 23 is cross-sectional view of a depot in accordance with someembodiments of the present technology.

FIG. 24A is a perspective view of a depot in accordance with someembodiments of the present technology.

FIG. 24B is cross-sectional view of the depot shown in FIG. 24A takenalong line B-B.

FIG. 24C is cross-sectional view of the depot shown in FIG. 24A takenalong line C-C.

FIG. 24D is a perspective view of a depot in accordance with someembodiments of the present technology.

FIG. 25 is a perspective view of a depot in accordance with someembodiments of the present technology.

FIG. 26 is a perspective view of a depot in accordance with someembodiments of the present technology.

FIG. 27 is a perspective view of a depot in accordance with someembodiments of the present technology.

FIG. 28 is a perspective view of a depot in accordance with someembodiments of the present technology.

FIG. 29A is a side cross-sectional view of a depot in accordance withsome embodiments of the present technology.

FIG. 29B is a cross-sectional view of the depot shown in FIG. 29A takenalong line B-B.

FIG. 30 is a side cross-sectional view of a depot in accordance withsome embodiments of the present technology.

FIG. 31 is a side cross-sectional view of a depot in accordance withsome embodiments of the present technology.

FIG. 32 is a perspective view of a depot in accordance with someembodiments of the present technology.

FIG. 33 is a side cross-sectional view of a depot in accordance withsome embodiments of the present technology.

FIG. 34 is a side cross-sectional view of a depot in accordance withsome embodiments of the present technology.

FIG. 35 is a side cross-sectional view of a depot in accordance withsome embodiments of the present technology.

FIG. 36A is a side cross-sectional view of a depot in accordance withsome embodiments of the present technology.

FIG. 36B is a cross-sectional view of the depot shown in FIG. 36A takenalong line B-B.

FIG. 36C is a side cross-sectional view of a depot in accordance withsome embodiments of the present technology.

FIG. 36D is a side cross-sectional view of a depot in accordance withsome embodiments of the present technology.

FIG. 37A is a side cross-sectional view of a depot in accordance withsome embodiments of the present technology.

FIG. 37B depicts example release profiles over time of the depot shownin FIG. 37A.

FIG. 38A is a side cross-sectional view of a depot in accordance withsome embodiments of the present technology.

FIG. 38B depicts example release profiles over time of the depot shownin FIG. 38A.

FIG. 39A is a side cross-sectional view of a depot in accordance withsome embodiments of the present technology.

FIG. 39B depicts example release profiles over time of the depot shownin FIG. 39A.

FIG. 40A is a perspective view of a depot in accordance with someembodiments of the present technology.

FIG. 40B is a perspective view of a depot in accordance with someembodiments of the present technology.

FIG. 41A is a side view of a depot in a straightened state in accordancewith some embodiments of the present technology.

FIG. 41B is a side view of the depot shown in FIG. 41A in a curvedstate.

FIG. 42A is a side view of a depot in a straightened state in accordancewith some embodiments of the present technology.

FIG. 42B is a side view of the depot shown in FIG. 42A in a curvedstate.

FIG. 43A is a perspective view of a depot in a straightened state inaccordance with some embodiments of the present technology.

FIG. 43B is cross-sectional view of the depot shown in FIG. 43A takenalong line B-B.

FIG. 43C is a side view of the depot shown in FIG. 43A in a curvedstate.

FIG. 44 is a side view of a depot deployed at a target site in a body inaccordance with some embodiments of the present technology.

FIG. 45 is a side view of a depot deployed at a target site in a body inaccordance with some embodiments of the present technology.

FIG. 46 is a side view of a depot in accordance with some embodiments ofthe present technology.

FIG. 47 is a side view of a depot in accordance with some embodiments ofthe present technology.

FIGS. 48A and 48B are perspective views of depots in accordance withsome embodiments of the present technology.

FIG. 49A-C are perspective, top, and side views, respectively, of adepot in accordance with some embodiments of the present technology.

FIG. 50A is an end view of a depot in a curled state in accordance withsome embodiments of the present technology.

FIG. 50B is a side view of the depot shown in FIG. 50A in an uncurledstate.

FIG. 51 illustrates a plurality of depots in accordance with someembodiments of the present technology.

FIG. 52A is an end view of a plurality of depots in accordance with someembodiments of the present technology.

FIG. 52B is a side view of the depots shown in FIG. 52A.

FIG. 52C illustrates a method of manufacturing the depots shown in FIGS.52A and 52B.

FIG. 53 depicts the in vitro release profile for the depots as describedin Example 1, in accordance with the present technology.

FIG. 54 depicts the in vitro release profile for the depots as describedin Example 2A, in accordance with the present technology.

FIG. 55 depicts the in vitro release profile for the depots as describedin Example 2B, in accordance with the present technology.

FIG. 56 depicts the in vitro release profile for the depots as describedin Example 3, in accordance with the present technology.

FIG. 57A shows the in vivo blood plasma bupivacaine concentration overtime for a rabbit implanted with the depots as described in Example 4,in accordance with the present technology.

FIG. 57B depicts the in vitro release profile over time for the sampledepots as described in Example 4, in accordance with the presenttechnology.

FIG. 57C shows the in vivo blood plasma bupivacaine concentration overtime for a rabbit implanted with the depots as described in Example 4,in accordance with the present technology.

FIG. 57D depicts the in vitro release profile over time of the sampledepots as described in Example 4, in accordance with the presenttechnology.

FIG. 58 shows the in vivo blood plasma bupivacaine concentration overtime for a canine implanted with the depots as described in Example 5,in accordance with the present technology.

FIG. 59A shows the in vivo blood plasma bupivacaine concentration overtime for a sheep implanted with the depots as described in Example 6, inaccordance with the present technology.

FIG. 59B shows the in vivo synovial bupivacaine concentration over timefor a sheep implanted with the depots as described in Example 6, inaccordance with the present technology.

FIG. 59C is a plot depicting the blood plasma bupivacaine concentrationversus the synovial bupivacaine concentration over time for a sheepimplanted with the depots as described in Example 6, in accordance withthe present technology.

FIGS. 60A and 60B are tables showing details of the sample depots usedin Example 7.

FIG. 60C shows the in vivo blood plasma bupivacaine concentration overtime for a sheep implanted with the depots as described in Example 7, inaccordance with the present technology.

FIG. 60D shows the in vivo synovial bupivacaine concentration over timefor a sheep implanted with the depots as described in Example 7, inaccordance with the present technology.

FIG. 60E shows the acute and subacute average daily AUC for the sampledepots of Example 7.

FIG. 60F is a plot depicting the blood plasma bupivacaine concentrationversus the synovial bupivacaine concentration over time for a sheepimplanted with the depots as described in Example 7, in accordance withthe present technology.

FIG. 61A shows the in vivo blood plasma bupivacaine concentration overtime for a sheep implanted with the depots as described in Example 8, inaccordance with the present technology.

FIG. 61B shows the in vivo synovial bupivacaine concentration over timefor a sheep implanted with the depots as described in Example 8, inaccordance with the present technology.

FIGS. 62A and 62B illustrate common locations within a patient that maybe sites where surgery is conducted and locations where the depot can beadministered.

FIG. 63 is a table showing common surgical procedures for which thedepots of the present technology may be utilized for treatingpostoperative pain. FIG. 63 also shows nerve targets and anatomicalaccess/placement associated with the different surgeries.

FIGS. 64A-64C are anterior, lateral, and medial views of a human knee,showing the location of the nerves innervating the knee.

FIG. 65A is a splayed view of a human knee exposing the intracapsularspace and identifying potential locations for positioning one or moredepots.

FIG. 65B is a splayed view of a human knee exposing the intracapsularspace and showing several depots positioned within for treatingpostoperative pain.

FIGS. 66A and 66B show anterior and posterior, extracapsular views of ahuman knee, showing the location of the nerves innervating the knee atan extracapsular location.

FIG. 67 is an anterior view of a partially-splayed human knee, showingan extracapsular space and showing several depots of the presenttechnology positioned at the extracapsular space for treatingpostoperative pain.

DETAILED DESCRIPTION

The present technology relates to implantable depots for the sustained,controlled release of therapeutic agents, and associated devices,systems, and methods of use. Examples of the depots of the presenttechnology and associated release kinetics are described below withreference to FIGS. 2-52C and Section I. Selected examples of the depotsof the present technology and associated release profiles are describedbelow with reference to FIGS. 53-61B and Section II. Selected devices,systems, and methods for using the depots of the present technology fortreating postoperative pain associated with orthopedic surgery aredescribed below with reference to FIGS. 62A-67 and Section III. Selecteddevices, systems, and methods for using the depots of the presenttechnology for treating postoperative pain associated with othersurgeries are described below at Section IV.

I. Examples of Depots of the Present Technology

As noted previously, prior art drug delivery systems often suffer from alack of a true controlled release mechanism in that they typicallyprovide a burst of drug upon contact with surrounding physiologic fluidsfollowed by a residual release of drug. For example, FIG. 1 shows anexample prior art biodegradable polymer-based delivery system, in whichthe drug concentration in plasma peaked within 15 hours of implantation,thereby illustrating a duration of effect that is inadequate.

Disclosed herein are implantable depots and associated devices, systems,and methods for treating (i.e., preventing, reducing, and/oreliminating) postoperative pain via sustained, controlled release of atherapeutic agent while the depot is implanted at a treatment site invivo. Many embodiments of the present technology comprise one or moredepots configured to be implanted at or near a surgical site of apatient to treat pain following a surgery. While implanted in vivo, thedepot(s) are configured to release a therapeutic agent (such as ananalgesic) to the surgical site in a controlled, prescribed manner forat least 3 days following implantation.

As used herein, a “depot” comprises a composition configured toadminister at least one therapeutic agent to a treatment site in thebody of a patient in a controlled, sustained manner. The depot alsocomprises the therapeutic agent itself. A depot may comprise a physicalstructure or carrier to configured to perform or enhance one or morefunctions related to treatment, such as facilitating implantation and/orretention in a treatment site (e.g., tissue at the intracapsular and/orextracapsular space of a knee joint), modulating the release profile ofthe therapeutic agent (e.g., creating a two-phase release profile),increasing release towards a treatment site, reducing release away froma treatment site, or combinations thereof. In some embodiments, a“depot” includes but is not limited to films, sheets, strips, ribbons,capsules, coatings, matrices, wafers, pills, pellets, or otherpharmaceutical delivery apparatus or a combination thereof. Moreover, asused herein, “depot” may refer to a single depot, or may refer tomultiple depots. As an example, the statement “The depot may beconfigured to release 2 g of therapeutic agent to a treatment site”describes (a) a single depot that is configured to release 2 g oftherapeutic agent to a treatment site, and (b) a plurality of depotsthat collectively are configured to release 2 g of therapeutic agent toa treatment site.

FIG. 2 is an isometric view of an implantable depot 100 in accordancewith several embodiments of the present technology. The depot 100 may bea thin, multi-layered polymer film configured to be implanted at atreatment site comprising a therapeutic region 200 containing atherapeutic agent (such as an analgesic), and a control region 300configured to regulate the release of the therapeutic agent from thedepot 100 in a controlled and sustained manner. The depot 100 mayinclude a high therapeutic payload of the therapeutic agent, especiallyas compared to other known films of equal thickness or polymer weightpercentage, while exhibiting mechanical properties (e.g., flexuralstrength) sufficient to withstand storage, handling, implantation,and/or retention in the treatment site. For example, in someembodiments, the depot 100 comprises at least 50% by weight of thetherapeutic agent.

The control region 300 may comprise at least one bioresorbable polymerand at least one releasing agent mixed with the polymer, and thetherapeutic region 200 may comprise at least one bioresorbable polymerand at least one releasing agent mixed with the polymer and thetherapeutic agent. The control region 300 may optionally include atherapeutic agent, or the control region 300 may include no therapeuticagent at all. The therapeutic region 200 may optionally include noreleasing agent at all. The releasing agent in the control region 300may be the same or may be different from the releasing agent in thetherapeutic region 200. The bioresorbable polymer in the control region300 may be the same or may be different from the bioresorbable polymerin the therapeutic region 200. As detailed below, in some embodimentsthe therapeutic region 200 and/or the control region 300 may havedifferent constituents and/or formulations.

When exposed to a fluid (e.g., physiologic fluid), the releasing agentcan have a dissolution rate that is faster than the degradation rate ofthe bioresorbable polymer. Accordingly, when a fluid contacts the depot100 (e.g., after implantation of the depot 100 in a treatment site), thereleasing agent dissolves within the surrounding polymer of the controlregion 300 and/or therapeutic region 200 faster than the polymerdegrades. As the releasing agent dissolves, the space vacated by thedissolved releasing agent forms diffusion openings (e.g., channels,voids, pores, etc.) in the surrounding polymer region. The formation ofdiffusion openings may enhance the release of therapeutic agent from thepolymer region and into the surrounding physiologic fluid. In someembodiments, the release rate of the therapeutic agent is higher whenthere are diffusion openings in the polymer region, compared to whenthere are no diffusion openings in the polymer region.

The concentration and type of releasing agent, among other parameters,can be selected to regulate the release of the therapeutic agent fromthe therapeutic region 200 and/or through the control region 300 intothe surrounding fluid at a controlled dosage rate over a desired periodof time. For example, a higher concentration of releasing agent mayincrease the release rate of the therapeutic agent, while a lowerconcentration of releasing agent may decrease the release rate of thetherapeutic agent. The therapeutic region 200 may comprise a differentconcentration and/or type of releasing agent than the control region300, or may comprise the same concentration and/or type of releasingagent.

The position and/or geometry of the control region 300 can be configuredto modulate the release profile of the therapeutic agent from thetherapeutic region 200. As shown in FIG. 2, at least a portion of thecontrol region 300 may be disposed on or adjacent the therapeutic region200 such that, when the depot 100 is initially positioned in vivo, thecontrol region 300 is between at least a portion of the therapeuticregion 200 and physiologic fluids at the treatment site. For example,the control region 300 can cover all or a portion of one or moresurfaces of the therapeutic region 200. When the depot 100 is exposed tophysiologic fluids, the therapeutic agent elutes from the exposedsurfaces of the therapeutic region 200 and through the control region300 by way of the diffusion openings created by dissolution of thereleasing agent. In general, the therapeutic agent elutes from theexposed surfaces of the therapeutic region 200 at a faster (e.g.,greater) rate than through the control region 300. As a result, thecontrol region 300 prolongs the release of the therapeutic agent fromthe therapeutic region 200 to provide for longer release times andregulates the dosage rate, e.g., to provide the desired degree of painrelief and avoid complications related to overdosing.

The depot of the present technology is configured to release atherapeutic agent in a highly controlled, predetermined manner that isspecifically tailored to the medical condition being treated and thetherapeutic agent used. As described in greater detail below in SectionII, the release kinetics of the depots may be customized for aparticular application by varying one or more aspects of the depot'scomposition and/or structure, such as the shape and/or size of thedepot, therapeutic region 200, and/or control region 300; the exposedsurface area of the therapeutic region 200; the type of polymer (in thetherapeutic region 200 and/or in the control region 300); the weightpercentage of the therapeutic agent, the polymer, and/or the releasingagent (within a particular region or generally throughout the depot100); and the composition of the therapeutic region 200 and the controlregion 300.

As shown in FIG. 3, in many embodiments the depot 100 (or a system ofdepots 100) is configured to release a disproportionately larger volumeof a therapeutic agent per day for a first period of time than for alonger second period of time. In some embodiments, the depot 100 (or asystem of depots 100) is configured to release the therapeutic agent forat least 14 days post-implantation (or post-immersion in a fluid), wherea controlled burst of about 20% to about 50% of the therapeutic agentpayload is released in the first 3-5 days, and at least 80% of theremaining therapeutic agent payload is released at a slower rate overthe last 10-11 days. In some embodiments, at least 90% of thetherapeutic agent payload is released by the end of 14 days.

A two-stage, second-order release profile—such as that shown in FIG.3—may be especially beneficial in the context of treating pain resultingfrom a total knee arthroplasty (“TKA”). TKA patients typicallyexperience the greatest pain within the first 1-3 days following surgery(clinically referred to as “acute pain”) with increasingly less painover the next 7-10 days (clinically referred to as “subacute pain”). Theacute period often overlaps or coincides with the patient's inpatientcare (usually 1-3 days), and the subacute period generally begins whenthe patient is discharged and returns home. The two-stage, second-orderrelease profile shown in FIG. 3 is also beneficial for other surgicalapplications, such as other orthopedic applications (e.g., ligamentrepair/replacement and other damage to the knee, shoulder, ankle, etc.)or non-orthopedic surgical applications. Excessive pain following anysurgery may extend inpatient care, cause psychological distress,increase opioid consumption, and/or impair patient participation inphysical therapy, any of which may prolong the patient's recovery and/ormitigate the extent of recovery. Pain relief during the subacute periodmay be particularly complicated to manage, as patient compliance withthe prescribed pain management regimen drops off when patientstransition from an inpatient to home environment.

To address the foregoing challenges in post-surgical pain management,the depot 100 (or depot system comprising multiple depots 100) of thepresent technology may have a release profile tailored to meet the painmanagement needs specific to the acute and subacute periods. Forexample, to address the greater acute pain that occurs immediatelyfollowing surgery, the depot 100 may be configured to release thetherapeutic agent at a faster rate for the first 3-5 days afterimplantation (as shown in FIG. 3) compared to a subsequent period of9-11 days. In some embodiments, the depot 100 may deliver a localanesthetic at a rate of from about 150 mg/day to about 400 mg/day duringthis first, acute period. To address the diminishing pain during thesubacute period, the depot 100 may be configured to release thetherapeutic agent at a slower rate for the remaining 9-11 days. In someembodiments, the depot 100 may deliver a local anesthetic at a rate offrom about 50 mg/day to about 250 mg/day during this second, subacuteperiod. In some embodiments, the rate of release continuously decreasesthroughout the first period and/or the second period.

The release profile of the depot 100 may be tuned to release atherapeutic agent for other durations and/or at other release rates byadjusting the structure, composition, and the process by which the depotis manufactured. For example, in some embodiments the depot 100 may beconfigured to release the therapeutic agent at a constant ratethroughout the entire duration of release. In particular embodiments,the depot 100 may be configured to release the therapeutic agent at aconstant rate for a first period of time and at a non-constant rate fora second period of time (which may occur before or after the firstperiod of time).

In some embodiments, the depot 100 is configured to release no more than20%, no more than 25%, no more than 30%, no more than 35%, no more than40%, no more than 45%, no more than 50%, no more than 55%, no more than60%, no more than 65%, or no more than 70% of the therapeutic agent inthe first day, 2 days, 3 days, 4 days, 5 days, 6 days, 8 days, 9 days,10 days, 11 days, 12 days, or 13 days of the duration of release, andwherein at least 75%, at least 80%, at least 85%, at least 90%, at least95%, or 100% of the remaining therapeutic agent is released in theremaining days of the duration of release. The intended duration ofrelease may be at least 1 day, at least 2 days, at least 3 days, atleast 4 days, at least 5 days, at least 6 days, at least 7 days, atleast 8 days, at least 9 days, at least 10 days, at least 11 days, atleast 12 days, at least 13 days, at least 14 days, at least 15 days, atleast 16 days, at least 17 days, at least 18 days, at least 19 days, atleast 20 days, at least 21 days, at least 22 days, at least 23 days, atleast 24 days, at least 25 days, at least 26 days, at least 27 days, atleast 28 days, at least 29 days, or at least 30 days.

In some embodiments, the depot 100 is configured to release at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% ofthe therapeutic agent in the depot 100 within the intended duration oftreatment. The intended duration of treatment may be at least 1 day, atleast 2 days, at least 3 days, at least 4 days, at least 5 days, atleast 6 days, at least 7 days, at least 8 days, at least 9 days, atleast 10 days, at least 11 days, at least 12 days, at least 13 days, atleast 14 days, at least 15 days, at least 16 days, at least 17 days, atleast 18 days, at least 19 days, at least 20 days, at least 21 days, atleast 22 days, at least 23 days, at least 24 days, at least 25 days, atleast 26 days, at least 27 days, at least 28 days, at least 29 days, atleast 30 days, at least 40 days, at least 50 days, at least 60 days, atleast 70 days, at least 90 days, at least 100 days, at least 200 days,at least 300 days, or at least 365 days.

In some embodiments, the depot 100 is configured to release from about50 mg/day to about 600 mg/day, 100 mg/day to about 500 mg/day, or fromabout 100 mg/day to about 400 mg/day, or from about 100 mg/day to about300 mg/day of the therapeutic agent to the treatment site. In general,the release rate can be selected to deliver the desired dosage toprovide the extent of pain relief needed at a given time after thesurgical procedure, control toxicity, and deliver the therapeutic agentfor a sufficient period of time for pain relief.

In some embodiments, the depot 100 is configured to release from about50 mg/day to about 600 mg/day, from about 100 mg/day to about 500mg/day, or from about 100 mg/day to about 400 mg/day, or from about 100mg/day to about 300 mg/day of the therapeutic agent to the treatmentsite within a first period of release. The depot 100 can further beconfigured to release from about 500 mg/day to about 600 mg/day, about100 mg/day to about 500 mg/day, or from about 100 mg/day to about 400mg/day, or from about 100 mg/day to about 300 mg/day of the therapeuticagent to the treatment site within a second period of release. Therelease rate during the first period may be the same as, different than,less than, or greater than the release rate during the second period.Moreover, the first period may be longer or shorter than the secondperiod. The first period may occur before or after the second period.

In some embodiments, the depot 100 is configured to release no more than50 mg, no more than 100 mg, no more than 150 mg, no more than 200 mg, nomore than 250 mg, no more than 300 mg, no more than 350 mg, no more than400 mg, no more than 450 mg, no more than 500 mg, no more than 600 mg,no more than 700 mg, no more than 800 mg, no more than 900 mg, no morethan 1000 mg, at least 10 mg, at least 20 mg, at least 30 mg, at least40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg,at least 90 mg, at least 100 mg, at least 110 mg, at least 120 mg, atleast 130 mg, at least 140 mg, at least 150 mg, at least 160 mg, atleast 170 mg, at least 180 mg, at least 190 mg, at least 200 mg, atleast 210 mg, at least 220 mg, at least 230 mg, at least 240 mg, atleast 250 mg, at least 260 mg, at least 270 mg, at least 280 mg, atleast 290 mg, or at least 300 mg of the therapeutic agent within any dayof a first period of release. This may be useful for providing differentdegrees of pain relief at different times after the surgical procedure,and it may also be useful to control toxicity. In such embodiments, thedepot 100 may be configured to release no more than 50 mg, no more than100 mg, no more than 150 mg, no more than 200 mg, no more than 250 mg,no more than 300 mg, no more than 350 mg, no more than 400 mg, no morethan 450 mg, no more than 500 mg, no more than 600 mg, no more than 700mg, no more than 800 mg, no more than 900 mg, no more than 1000 mg, atleast 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, at least 50mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, atleast 100 mg, at least 110 mg, at least 120 mg, at least 130 mg, atleast 140 mg, at least 150 mg, at least 160 mg, at least 170 mg, atleast 180 mg, at least 190 mg, at least 200 mg, at least 210 mg, atleast 220 mg, at least 230 mg, at least 240 mg, at least 250 mg, atleast 260 mg, at least 270 mg, at least 280 mg, at least 290 mg, or atleast 300 mg of the therapeutic agent within any day of a second periodof release. The first period of release and/or the second period ofrelease may be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days. The depot100 may be configured to release the therapeutic agent at a first rateduring the first period and at a second rate during the second period.The first rate may be the same as, different than, less than, or greaterthan the second rate. In some embodiments, the first rate is at least2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or10-fold greater than the second rate, or vice versa. Moreover, the firstperiod may be longer or shorter than the second period. The first periodmay come before or after the second period.

In some embodiments, the depot 100 is configured to release no more than50 mg, no more than 100 mg, no more than 150 mg, no more than 200 mg, nomore than 250 mg, no more than 300 mg, no more than 350 mg, no more than400 mg, no more than 450 mg, no more than 500 mg, no more than 600 mg,no more than 700 mg, no more than 800 mg, no more than 900 mg, or nomore than 1000 mg of therapeutic agent within any day of the duration ofrelease.

In some embodiments, the depot 100 is configured to release thetherapeutic agent at a treatment site in vivo and/or in the presence ofone or more fluids for no less than 1 day, no less than 2 days, no lessthan 3 days, no less than 4 days, no less than 5 days, no less than 6days, no less than 7 days, no less than 8 days, no less than 9 days, noless than 10 days, no less than 11 days, no less than 12 days, no lessthan 13 days, no less than 14 days, no less than 15 days, no less than16 days, no less than 17 days, no less than 18 days, no less than 19days, no less than 20 days, no less than 21 days, no less than 22 days,no less than 23 days, no less than 24 days, no less than 25 days, noless than 26 days, no less than 27 days, no less than 28 days, no lessthan 29 days, no less than 30 days, no less than 40 days, no less than50 days, no less than 60 days, no less than 70 days, no less than 90days, no less than 100 days, no less than 200 days, no less than 300days, or no less than 365 days.

The release kinetics of the depots of the present technology may betuned for a particular application by varying one or more aspects of thedepot's structure and/or composition, such as the exposed surface areaof the therapeutic region 200, the porosity of the control region 300during and after dissolution of the releasing agent, the concentrationof the therapeutic agent in the therapeutic region, thepost-manufacturing properties of the polymer, the structural integrityof the depots to avoid a sudden release of the therapeutic agent, therelative thicknesses of the therapeutic region 200 compared to thecontrol region 300, and other properties of the depots. Severalembodiments of depots of the present technology combine one or more ofthese properties in a manner that produces exceptional two-phase releaseprofiles in animal studies that significantly outperform existinginjectable or implantable systems, while also overcoming theshortcomings of disclosed prophetic devices. For example, severalembodiments have exhibited two-phase release profiles that deliver anadequate mass of therapeutic agent to treat pain associated with jointreplacement surgery or other applications over a 14-day period whilemaintaining sufficient structural integrity to withstand the forces of ajoint to avoid a sudden release of too much therapeutic agent. Thissurprising result enables depots of the present technology to at leastreduce, if not replace, opioids and/or enhance other existing painrelief systems for orthopedic surgical applications, non-orthopedicsurgical applications, and for other applications (e.g., oncological).

For example, the release profile can be tuned by, at least in part,controlling the amount of exposed surface area of the therapeutic region200 because depots having a therapeutic region 200 covered onlypartially by a control region 300 (see, for example, FIGS. 2,4-8, and13) will generally release a higher proportion of the total payload overa shorter period of time as compared to embodiments where thetherapeutic region 200 is completely encapsulated by the control region300 (see, for example, FIGS. 9A-12). More specifically, depot designshaving a therapeutic region 200 with exposed surfaces will typicallyrelease the therapeutic agent at a high, substantially linear rate for afirst period of time and then at a lower, substantially linear rate fora second period of time. Alternatively, depot designs having atherapeutic region 200 with surfaces that are substantially covered byone or more control regions 300 may achieve a zero-order release suchthat the release of the payload of therapeutic agent is at substantiallythe same rate.

As shown in FIG. 4, in some embodiments the depot 100 may comprise amulti-layer polymer film having a therapeutic region 200 and first andsecond control regions 300 a, 300 b positioned at opposite surfaces 100a, 100 b of the therapeutic region 200. The depot 100 may be in the formof a flexible, rectangular strip having a length L, a width W, and aheight H (or thickness). In some embodiments, the depot 100 has (a) alength L of from about 5-40 mm, about 10-30 mm, about 15-20 mm, about20-35 mm, about 20-30 mm, about 20-25 mm, about 26-30 mm, about 5 mm,about 10 mm, about 11 mm, about 12 mm, about 13 mm, about 14 mm, about15 mm, about 16 mm, about 17 mm, about 18 mm, about 19 mm about 20 mm,about 21 mm, about 22 mm, about 23 mm, about 24 mm, about 25 mm, about26 mm, about 27 mm, about 28 mm, about 29 mm, about 30 mm, about 10-15mm, about 12-16 mm, about 15-20 mm, about 21-23 mm, about 22-24 mm,about 23-25 mm, about 24-26 mm, about 25-27 mm, about 26-28 mm, about27-29 mm, or about 28-30 mm, (b) a width W of from about 5-40 mm, about10-30 mm, about 15-20 mm, about 20-35 mm, about 20-30 mm, about 20-25mm, about 26-30 mm, about 5 mm, about 10 mm, about 11 mm, about 12 mm,about 13 mm, about 14 mm, about 15 mm, about 16 mm, about 17 mm, about18 mm, about 19 mm about 20 mm, about 21 mm, about 22 mm, about 23 mm,about 24 mm, about 25 mm, about 26 mm, about 27 mm, about 28 mm, about29 mm, about 30 mm, about 10-15 mm, about 12-16 mm, about 15-20 mm,about 21-23 mm, about 22-24 mm, about 23-25 mm, about 24-26 mm, about25-27 mm, about 26-28 mm, about 27-29 mm, or about 28-30 mm (c) a heightH of from about 0.4 mm to about 4 mm, about 1 mm to about 3 mm, about 1mm to about 2 mm, at least 0.4 mm, at least 0.5 mm, at least 0.6 mm, atleast 0.7 mm, at least 0.8 mm, at least 0.9 mm, at least 1 mm, at least1.2 mm, at least 1.4 mm, at least 1.5 mm, at least 1.6 mm, at least 1.7mm, at least 1.8 mm, at least 2 mm, at least about 3 mm, no more than0.5 mm, no more than 0.6 mm, no more than 0.7 mm, no more than 0.8 mm,no more than 0.9 mm, etc.). In some embodiments, the depot 100 may havea L×W×H of about 26 mm×about 16 mm×about 1 mm, and in some embodiments,about 27 mm×about 17 mm×about 1 mm. In some embodiments, the depot 100may have other shapes and/or dimensions, such as those detailed below

Additionally, some embodiments of the depot shown in FIG. 4 areconfigured such that a thickness of the control regions 300 a and 300 b,either individually or collectively, is less than or equal to 1/10 of athickness of the therapeutic region 200. The thickness of the controlregions 300 a and 300 b, either individually or collectively, canfurther be no more than 1/12.5, 1/15, 1/17.5, 1/20, 1/22.5, 1/25, 1/30,1/40, 1/50, 1/75, or 1/100 of the thickness of the therapeutic region200. In those embodiments with multiple sub-control regions, one or moreof the sub-control regions may individually be less than or equal to1/10, 1/12.5, 1/15, 1/17.5, 1/20, 1/22.5, 1/25, 1/27.5, 1/30, 1/32.5,1/35, 1/37.5, 1/40, 1/42.5, 1/45, 1/47.5, 1/50, 1/55, 1/60, 1/65, 1/70,1/75, 1/80, 1/85, 1/90, 1/95, or 1/100 of a thickness of the therapeuticregion. In those embodiments where the control region comprises a singlecontrol region, the control region may have a thickness that is lessthan or equal to 1/10, 1/12.5, 1/15, 1/17.5, 1/20, 1/22.5, 1/25, 1/27.5,1/30, 1/32.5, 1/35, 1/37.5, 1/40, 1/42.5, 1/45, 1/47.5, 1/50, 1/55,1/60, 1/65, 1/70, 1/75, 1/80, 1/85, 1/90, 1/95, or 1/100 of a thicknessof the therapeutic region. In those embodiments with multiplesub-control regions, one or more of the sub-control regions mayindividually be less than or equal to 1/10, 1/12.5, 1/15, 1/17.5, 1/20,1/22.5, 1/25, 1/27.5, 1/30, 1/32.5, 1/35, 1/37.5, 1/40, 1/42.5, 1/45,1/47.5, 1/50, 1/55, 1/60, 1/65, 1/70, 1/75, 1/80, 1/85, 1/90, 1/95, or1/100 of a thickness of the depot. In those embodiments where thecontrol region comprises a single control region, the control region mayhave a thickness that is less than or equal to 1/10, 1/12.5, 1/15,1/17.5, 1/20, 1/22.5, 1/25, 1/27.5, 1/30, 1/32.5, 1/35, 1/37.5, 1/40,1/42.5, 1/45, 1/47.5, 1/50, 1/55, 1/60, 1/65, 1/70, 1/75, 1/80, 1/85,1/90, 1/95, or 1/100 of a thickness of the depot.

The control regions 300 a, 300 b may only cover a portion of thetherapeutic region 200 such that a portion of each of the lateralsurfaces (e.g., sidewall) of the therapeutic region 200 is exposed tophysiologic fluids immediately upon implantation of the depot 100 invivo. For example, at least prior to implantation, the exposed surfacesof the therapeutic region 200 may account for about 2% to about 15%,about 3% to about 12%, about 5% to about 10%, about 6% to about 8%,about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%,about 9%, about 10% of the surface area of the depot 100. In someembodiments, at least prior to implantation, the ratio of the exposedsurfaces of the therapeutic region 200 to the exposed surfaces of thecontrol region 300 may be about 2% to about 15%, about 3% to about 12%,about 5% to about 10%, about 6% to about 8%, about 2%, about 3%, about4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% of thesurface area of the depot 100.

When the depot 100 is exposed to physiologic fluids (or any similarfluid in an in vitro setting), the therapeutic agent will elute from theexposed surfaces 202 (in addition to through the control regions 300 a,300 b), such that the therapeutic agent is released faster than if thetherapeutic region 200 had no exposed regions. As such, the surface areaof the exposed surfaces 202 may be tailored to provide an initial,controlled burst, followed by a tapering release (for example, similarto that shown at FIG. 3). The initial, more aggressive release of thetherapeutic agent is slowed in part by the control regions 300 a, 300 bthat initially reduce the surface area of the therapeutic region 200exposed to the fluids. Unlike the depots 100 of the present technology,many conventional drug-eluting technologies provide an initial,uncontrolled burst release of drug when exposed to physiologic fluids.Several embodiments of depots of the present technology not only enableenough therapeutic agent to be implanted for several days' or weeks'worth of dosage to achieve a sustained, durable, in vivo pharmacologicaltreatment, but they also release the therapeutic agent as prescribed andthereby prevent a substantial portion of the entire payload beingreleased in an uncontrolled manner that could potentially result incomplications to the patient and/or reduce the remaining payload suchthat there is not enough therapeutic agent remaining in the depot todeliver a therapeutic amount for the remaining duration of release.

In some embodiments, the depot 100 shown in FIG. 4 is configured suchthat about 20% to about 50% of the analgesic is released in the firstabout 3 days to about 5 days of the 14 days, and wherein at least 80% ofthe remaining analgesic is released in the last about 9 days to about 11days of the 14 days. This release profile provides higher dosages of thetherapeutic agent during the acute period after surgery compared to thesubacute period. In some embodiments, the depot 100 shown in FIG. 4 isconfigured to release about 100 mg to about 500 mg of analgesic to thetreatment site per day, and in some cases no more than 400 mg or no morethan 300 mg of analgesic per day within the first 3 days of implantationand no more than 200 mg per day in the remaining days.

Several embodiments of the depot 100 shown in FIG. 4 are also configuredto maintain their structural integrity even after a substantial portionof the releasing agent has eluted from the depot 100. As the releasingagent(s) dissolves and therapeutic agent(s) elutes, the functionalmechanical aspects of the depot 100 may change over time. Suchmechanical aspects include structural integrity, flexural strength,tensile strength, or other mechanical characteristics of the depot. If adepot 100 experiences too much degradation too fast, it may failmechanically and release an undesirable burst of therapeutic agent intothe body. Several embodiments of depots 100 shown in FIG. 4 are loadedwith enough therapeutic agent to deliver 100 mg to 500 mg of thetherapeutic agent per day while still being able to maintain itsstructural integrity such that depot remains largely intact up to atleast 14 days after implantation. A depot can be sufficiently intact,for example, if it does not fracture into multiple component pieces withtwo or more of the resulting pieces being at least 5% of the previoussize of the depot. Alternatively, or additionally, a depot can beconsidered to be sufficiently intact if the release rate of thetherapeutic agent does not increase by more than a factor of three ascompared to the release rate of therapeutic agent in a control depotsubmerged in a buffered solution.

The therapeutic agent can be at least 50%-95% by weight of the totalweight of the depot 100 before implantation, or 55%-85% by weight of thetotal weight of the depot 100 before implantation, or 60%-75% by weightof the total weight of the depot 100 before implantation. Likewise, thepolymer may be no more than 5%-50% by weight of the total weight of thedepot 100 before implantation, or 10%-50% by weight of the total weightof the depot 100 before implantation, or 15%-45% by weight of the totalweight of the depot 100 before implantation, or 20%-40% by weight of thetotal weight of the depot 100 before implantation, or no more than 25%,no more than 30%, no more than 35%, or no more than 40%. The ratio ofthe mass of the therapeutic agent in the depot 100 to the mass of thepolymer in the depot 100 can be at least 16:1, 15:1, 14:1, 13:1, 12:1,11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, or 2:1.

Several embodiments of the depot 100 shown in FIG. 4 having one or morecombinations of the parameters described in the preceding paragraphshave provided exceptional results in animal studies as described herein.For example, a depot 100 was configured such that (a) the thickness ofthe control regions 300 a-b were each or collectively less than or equalto 1/50 of the thickness of the therapeutic region 200, (b) the mass oftherapeutic agent payload was sufficient to release about 100 mg toabout 500 mg of analgesic to the treatment site per day, and (c) thestructural integrity was such that the depot remained largely intact forat least 14 days after implantation. These embodiments were able torelease about 20% to about 50% of the analgesic payload in the firstabout 3 days to about 5 days of the 14 days, and then release at least80% of the remaining analgesic payload in the last about 9 days to about11 days of the 14 days. This was unexpected because, at least in part,(a) providing such a large payload of therapeutic agent in thetherapeutic region was expected to cause the depot 100 fail mechanicallyon or before 14 days post-implant, and (b) no disclosed devices hadachieved a release profile wherein about 20% to about 50% of theanalgesic was released in the first about 3 days to about 5 days of the14 days, and then at least 80% of the remaining analgesic was releasedin the last about 9 days to about 11 days of the 14 days.

In some embodiments, one or more control regions 300 of the depot 100may comprise two or more sub-control regions. For example, as shown inFIG. 5, the depot 100 may have a first control region 300 a and a secondcontrol region 300 b, each of which comprises first and secondsub-control regions 302 a, 302 b and 302 c, 302 d, respectively. Thefirst and second control regions 300 a, 300 b and/or one, some or all ofthe sub-control regions 302 a-302 d may have the same or differentamounts of releasing agent, the same or different concentrations ofreleasing agent, the same or different releasing agents, the same ordifferent amounts of polymer, the same or different polymers, the sameor different polymer to releasing agent ratios, and/or the same ordifferent thicknesses. In some embodiments, the concentration of thereleasing agent in the individual outer control sub-regions 302 a, 302 dis less than the concentration of the releasing agent in the individualinner control sub-regions 302 b, 302 c such that the outer portion ofthe collective control region will elute the therapeutic agent moreslowly than the inner portion of the collective control region. In someembodiments, the concentration of the releasing agent in the individualouter control sub-regions 302 a, 302 d is greater than the concentrationof the releasing agent in the individual inner control sub-regions 302b, 302 c. In those embodiments where the control region includes morethan two sub-regions, the concentration of releasing agent persub-region or layer may increase, decrease, or remain constant as thesub-control regions are farther away from the therapeutic region 200.

In certain embodiments, the outer control sub-regions include at least5% by weight of the releasing agent, at least 10% by weight of thereleasing agent, at least 15% by weight of the releasing agent, at least20% by weight of the releasing agent, at least 25% by weight of thereleasing agent, at least 30% by weight of the releasing agent, at least35% by weight of the releasing agent, at least 40% by weight of thereleasing agent, at least 45% by weight of the releasing agent, or atleast 50% by weight of the releasing agent. In some embodiments, theinner control sub-regions include at least 5% by weight of the releasingagent, at least 10% by weight of the releasing agent, at least 15% byweight of the releasing agent, at least 20% by weight of the releasingagent, at least 25% by weight of the releasing agent, at least 30% byweight of the releasing agent, at least 35% by weight of the releasingagent, at least 40% by weight of the releasing agent, at least 45% byweight of the releasing agent, or at least 50% by weight of thereleasing agent. In some embodiments, the outer control sub-regions mayinclude a first amount of the releasing agent and the inner controlsub-regions may include a second amount of the releasing agent, wherethe second amount is at least 200%, at least 300%, at least 400%, or atleast 500% greater than the first amount.

FIGS. 6-8 show depot embodiments having a plurality of alternatingtherapeutic regions 200 and control regions 300 in accordance with thepresent technology. The depot 100 may have two or more control regions300 and/or sub-regions 302 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, etc.),and the depot 100 may have one or more therapeutic regions 200 and/orsub-regions 202 (e.g., 1, 2, 3, 4, 5, 6, 7, 10, 15, 20, etc.) surroundedby at least one control region 300 and/or sub-region 302. In someembodiments, each of the therapeutic regions 200 may comprise a singlelayer and/or each of the control regions 300 may comprise a singlelayer. In some embodiments, one, some, or all of the therapeutic regions200 may comprise multiple layers and/or one, some, or all of the controlregions 300 may comprise multiple layers. In some embodiments, forexample as shown in FIGS. 6 and 7, two or more sub-regions 302 a-b (FIG.6) and 302 a-b and 302 c-d (FIG. 7) may be adjacent to each otherbetween sub-regions 202 of the therapeutic region 200. Moreover, one ormore of the individual control regions 300 and/or one or more of thetherapeutic regions 200 may have the same or different amounts and/ortypes of releasing agent, and one or more of the therapeutic regions mayhave the same or different amounts and/or types of therapeutic agent.

The embodiments shown in FIGS. 6-8 may be beneficial where thetherapeutic region comprises a large payload of the therapeutic agent(e.g., equivalent to many days, weeks or months of dosage). Theseembodiments may be beneficial because, with such a large payload, shouldthe therapeutic region 200 be exposed to the body abruptly, the entirepayload may be released prematurely, subjecting the patient to anabnormally and undesirably high dose of the therapeutic agent. Forexample, if the integrity of the control region 300 were compromised,the patient may be exposed in vivo to the therapeutic agent at a higherrate than intended, potentially resulting in a clinical complication.Particularly with respect to the administration of local anesthetics(e.g., bupivacaine, ropivacaine, etc.), manufacturing guidelinesrecommend no more than 400 mg should be administered within a 24-hourperiod. However, multiple studies have demonstrated that doses higherthan 400 mg from extended release products are safe due to their slowerrelease over an extended period of time. Regardless, in the event that acontrol region 300 is compromised, it is desirable for the patient to besubjected only to a fraction of the total payload, whereby the fractionto which the patient is exposed if prematurely released would be withinsafety margins for the particular therapeutic agent. The structuralintegrity of the control regions 300, as well as that of the therapeuticregion(s) 200, is an important property for depots with large masses oftherapeutic agents that are to be delivered over a long period of time.

To address this concern, in some embodiments of the present technology,the depot 100 may comprise multiple therapeutic regions 200 separated byone or more control regions 300 (for example, as shown in FIGS. 6-8).Such a configuration allows the therapeutic agent in each therapeuticregion 200 (which carries a fraction of the total payload), to beindividually sequestered. In the event a particular control region iscompromised, only the fractional payload corresponding to thetherapeutic region associated with the compromised control region wouldprematurely release. For example, in some of the foregoing embodiments,the total payload of the depot 100 may be at least 100 mg, at least 150mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg,at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, orat least 1000 mg of therapeutic agent, such as an analgesic (e.g.,bupivacaine, ropivacaine, etc.). Likewise, in some embodiments thefractional payload of each therapeutic region or sub-region may be up to1%, up to 5%, up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, upto 40%, up to 50%, up to 60%, up to 70%, up to 80%, up to 90%, or up to100% of the total payload contained within the depot 100. As a result,if any single sub-region 202 of the therapeutic region 200 iscompromised, it can release only a proportionate fraction of the totalpayload of the depot.

In some embodiments, each of the therapeutic regions and each of thecontrol regions is a micro-thin layer, i.e., having a layer thicknessthat is less than 1 mm. In some embodiments, the depot comprises fromabout 2 to about 100 therapeutic regions, or from about 2 to about 50therapeutic regions, or from about 2 to about 10 therapeutic regions.

FIGS. 9A-11 show some aspects of the present technology in which thedepots 100 may have one or more therapeutic regions 200 completelyenclosed or surrounded by one or more control regions 300. In contrastto the previously described embodiments, at least one therapeutic regionof such fully-enclosed embodiments does not have any exposed surfacearea. For example, as shown in FIGS. 9A and 9B, in some embodiments thedepot 100 may comprise a therapeutic region 200 surrounded orfully-enclosed by a control region 300 such that no portion of thetherapeutic region 200 is exposed through the control region 300. As aresult, the control region 300 substantially prevents contact betweenthe therapeutic agent and physiologic fluids, thereby preventing anuncontrolled, burst release of the therapeutic agent when implanted.Over time, the releasing agent imbedded in the polymer of the controlregion 300 contacts physiologic fluids and dissolves, thereby formingdiffusion openings in the control region. The combination of therestriction imposed by the control region and the diffusion openingsformed by dissolution of the releasing agent enables a controlledrelease of the therapeutic agent from the depot over the course ofseveral days, weeks, or months. Although the depot 100 is shown as arectangular, thin film in FIGS. 9A and 9B, in other embodiments thedepot 100 may have other shapes, sizes, or forms.

FIG. 10 illustrates a depot 100 having a therapeutic region 200fully-enclosed by a control region 300 having a first control region 300a and a second control region 300 b. As depicted in FIG. 10, in someembodiments the therapeutic region 200 may be sandwiched between thefirst control region 300 a and the second control region 300 b, and thefirst and second control regions 300 a-b may be bonded via heatcompression around the therapeutic region 200 to enclose the therapeuticregion 200 therebetween. In certain embodiments, a bioresorbable polymermay be wrapped around the entire depot and sealed on the top or bottomsurface creating a control region structure similar to that depicted inFIG. 9A. The outer portion of the first and second control regions 300a-b may be incorporated as the final wrapped layer to seal the edges.Additionally, the first and second control regions 300 a-b can beintegrally formed with each other using dip coating and/or spray coatingtechniques, such as dipping the therapeutic region 200 in a solution ofthe control region material or spraying a solution of control regionmaterial onto the surfaces of the therapeutic region 200.

In FIG. 10, the first control region 300 a can have first and secondsub-regions 302 a-b, and the second control region 300 b can have firstand second sub-regions 302 c-d. The first control region 300 a candefine a top control region member, and the first and second sub-regions302 a-b can comprise a first top control layer and a second top controllayer, respectively. The second control region 300 b can define a bottomcontrol region member, and the first and second sub-regions 302 c-d cancomprise a first bottom control layer and a second bottom control layer,respectively. The first and second top/bottom control layers can be anyvariation of the first and second control sub-regions discussed abovewith reference to FIG. 5. In addition, the first top control layer ofthe top control region member may have the same or different properties(e.g., thickness, polymer, releasing agent, concentration of releasingagent, total amount of releasing agent, polymer to releasing agentratio, etc.) as the first bottom control layer of the bottom controlregion member. Similarly, the second top control layer of the topcontrol region member may have the same or different properties as thesecond bottom control layer of the bottom control region member.Variations in the loading and construction of the layers may be designedinto the depot 100 to achieve a release profile or kinetics that suitsthe objectives of the intended therapy. In other embodiments, the firstcontrol region 300 a and/or the second control region 300 b has a singlelayer.

FIG. 11 shows some embodiments in which the depot 100 may have atherapeutic region 200 fully-enclosed by a control region 300 havingdifferent sub-region configurations. The depot 100 of FIG. 11 includes afirst control region 300 a and a second control region 300 b thattogether fully enclose the therapeutic region 200. In contrast to thedepot 100 shown in FIG. 10, the first control region 300 a has an outertop control region 301 a with first and second top sub-control regions302 a and 302 b, respectively, and an inner top control region 301 bwith first and second top layers 303 a and 303 b. The first and secondtop layers 303 a-b are over only the top surface of the therapeuticregion 200, while the first and second top sub-control regions 302 a-bcover a portion of the lateral surfaces of the therapeutic region 200and the inner top control region 301 b. The second control region 300 bhas an outer bottom control region 301 c with first and second bottomsub-control regions 302 c and 302 d, respectively, and an inner bottomcontrol region 301 d with first and second bottom layers 303 d and 303e, respectively. As such, when the depot 100 is positioned at thetreatment site in vivo, the outer top and bottom control regions 301 aand 301 c are between: (a) the therapeutic region 200 and the inner topand bottom control regions 301 b and 301 d, respectively, and (b)physiologic fluids at the treatment site. In certain embodiments, suchas that shown in FIG. 11, one or more of the outer top/bottom controlregions 301 a/301 c may comprise one or more control sub-regions, andone or more inner top/bottom control regions 301 b/301 d may include oneor more control sub-regions.

FIG. 12 shows a cross-section of a spherical depot 100 in accordancewith several embodiments of the present technology having a plurality ofalternating therapeutic regions 200 and control regions 300 inaccordance with the present technology. The depot 100 may have two ormore control regions 300 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, etc.),and the depot may have one or more therapeutic regions 200 (e.g., 1, 2,3, 4, 5, 6, 7, 10, 15, 20, etc.) surrounded by at least one controlregion 300. In some embodiments, each of the therapeutic regions 200 maycomprise a single layer and/or each of the control regions 300 maycomprise a single layer. In some embodiments, one, some, or all of thetherapeutic regions 200 may comprise multiple layers and/or one, some,or all of the control regions 300 may comprise multiple layers.Moreover, one or more of the individual control regions 200 and/or oneor more of the therapeutic regions 300 may have the same or differentamounts and/or types of releasing agent, and one or more of thetherapeutic regions 200 may have the same or different amounts and/ortypes of therapeutic agent.

FIG. 13 shows a depot 100 in accordance with several embodiments of thepresent technology having a therapeutic region 200 enclosed on the topand bottom surfaces as well as two of the four lateral surfaces by acontrol region 300. This configuration is expected to release thetherapeutic agent more slowly, at least initially, compared to a depotwith the same dimensions and fully exposed lateral surfaces (see, e.g.,the depot 100 shown in FIG. 4).

The release kinetics of the depots of the present technology may also betuned for a particular application by varying the shape and size of thedepot 100. Depending on the therapeutic dosage needs, anatomicaltargets, etc., the depot 100 can be different sizes, shapes, and formsfor implantation and/or injection in the body by a clinicalpractitioner. The shape, size, and form of the depot 100 should beselected to allow for ease in positioning the depot at the target tissuesite, and to reduce the likelihood of, or altogether prevent, the depotfrom moving after implantation or injection. This may be especially truefor depots being positioned within a joint (such as a knee joint),wherein the depot is a flexible solid that is structurally capable ofbeing handled by a clinician during the normal course of a surgerywithout breaking into multiple pieces and/or losing its general shape.Additionally, the depot may be configured to be placed in the knee of apatient and release the analgesic in vivo for up to 7 days withoutbreaking into multiple pieces.

Some of the form factors producible from the depot 100 or to be usedadjunctive to the depot for implantation and fixation into the bodyinclude: strips, ribbons, hooks, rods, tubes, patches, corkscrew-formedribbons, partial or full rings, nails, screws, tacks, rivets, threads,tapes, woven forms, t-shaped anchors, staples, discs, pillows, balloons,braids, tapered forms, wedge forms, chisel forms, castellated forms,stent structures, suture buttresses, coil springs, sponges, capsules,coatings, matrices, wafers, sheets, strips, ribbons, pills, and pellets.

The depot 100 may also be processed into a component of the form factorsmentioned in the previous paragraph. For example, the depot could berolled and incorporated into tubes, screws, tacks, or the like. In thecase of woven embodiments, the depot may be incorporated into amulti-layer woven film/braid/mesh wherein some of the filaments used arenot the inventive device. In one example, the depot is interwoven withDacron, polyethylene or the like. For the sake of clarity, any formfactor corresponding to the depot of the present technology, includingthose where only a portion or fragment of the form factor incorporatesthe depot, may be referred to herein as a “depot.”

As shown in the cross-sectional views of FIGS. 14A-14H, in variousembodiments, the depot 100 can be shaped like a sphere, a cylinder suchas a rod or fiber, a flat surface such as a disc, film, ribbon, strip orsheet, a paste, a slab, microparticles, nanoparticles, pellets, mesh orthe like. FIG. 14A shows a rectilinear depot 100. FIG. 14B shows acircular depot 100. FIG. shows a triangular depot 100. FIG. 14D showcross-like depot 100, FIG. 14E shows a star-like depot 100, and FIG. 14Fshows a toroidal depot 100. FIG. 14G shows a spheroid depot 100, andFIG. 14H shows a cylindrical depot 100. The shape of the depot 100 canbe selected according to the anatomy to fit within a given space andprovide the desired fixation and flexibility properties. This is becausethe fit, fixation and flexibility of the depot may enhance the ease ofimplanting the depot, ensure delivery of the therapeutic agent to thetarget site, and prolong the durability of the implant in dynamicimplant sites.

In various embodiments, the depot can be different sizes, for example,the depot may be a length of from about 0.4 mm to 100 mm and have adiameter or thickness of from about 0.01 to about 5 mm. In variousembodiments, the depot may have a layer thickness of from about 0.005 to5.0 mm, such as, for example, from 0.05 to 2.0 mm. In some embodiments,the shape may be a rectangular or square sheet having a ratio of widthto thickness in the range of 20 or greater, 25 or greater, 30 orgreater, 35 or greater, 40 or greater, 45 or greater, or 50 or greater.

In some embodiments, a thickness of the control region (a singlesub-control region or all sub-control regions combined) is less than orequal to 1/10, 1/12.5, 1/15, 1/17.5, 1/20, 1/22.5, 1/25, 1/27.5, 1/30,1/32.5, 1/35, 1/37.5, 1/40, 1/42.5, 1/45, 1/47.5, 1/50, 1/55, 1/60,1/65, 1/70, 1/75, 1/80, 1/85, 1/90, 1/95, or 1/100 of a thickness of thetherapeutic region. In those embodiments with multiple sub-controlregions, one or more of the sub-control regions may individually be lessthan or equal to 1/10, 1/12.5, 1/15, 1/17.5, 1/20, 1/22.5, 1/25, 1/27.5,1/30, 1/32.5, 1/35, 1/37.5, 1/40, 1/42.5, 1/45, 1/47.5, 1/50, 1/55,1/60, 1/65, 1/70, 1/75, 1/80, 1/85, 1/90, 1/95, or 1/100 of a thicknessof the therapeutic region. In those embodiments where the control regioncomprises a single control region, the control region may have athickness that is less than or equal to 1/10, 1/12.5, 1/15, 1/17.5,1/20, 1/22.5, 1/25, 1/27.5, 1/30, 1/32.5, 1/35, 1/37.5, 1/40, 1/42.5,1/45, 1/47.5, 1/50, 1/55, 1/60, 1/65, 1/70, 1/75, 1/80, 1/85, 1/90,1/95, or 1/100 of a thickness of the therapeutic region. In thoseembodiments with multiple sub-control regions, one or more of thesub-control regions may individually be less than or equal to 1/10,1/12.5, 1/15, 1/17.5, 1/20, 1/22.5, 1/25, 1/27.5, 1/30, 1/32.5, 1/35,1/37.5, 1/40, 1/42.5, 1/45, 1/47.5, 1/50, 1/55, 1/60, 1/65, 1/70, 1/75,1/80, 1/85, 1/90, 1/95, or 1/100 of a thickness of the depot. In thoseembodiments where the control region comprises a single control region,the control region may have a thickness that is less than or equal to1/10, 1/12.5, 1/15, 1/17.5, 1/20, 1/22.5, 1/25, 1/27.5, 1/30, 1/32.5,1/35, 1/37.5, 1/40, 1/42.5, 1/45, 1/47.5, 1/50, 1/55, 1/60, 1/65, 1/70,1/75, 1/80, 1/85, 1/90, 1/95, or 1/100 of a thickness of the depot.

In some embodiments, the depot 100 has a width and a thickness, and aratio of the width to the thickness is 21 or greater. In someembodiments, the ratio is 22 or greater, 23 or greater, 24 or greater,25 or greater, 26 or greater, 27 or greater, 28 or greater, 29 orgreater, 30 or greater, 35 or greater, 40 or greater, 45 or greater, or50 or greater.

In some embodiments, the depot 100 has a surface area and a volume, anda ratio of the surface area to volume is at least 1, at least 1.5, atleast 2, at least 2.5, or at least 3.

In any of the foregoing embodiments shown and described above withrespect to FIGS. 2-14H, dissolution of the releasing agent(s) andelution of the therapeutic agent(s) can change functional mechanicalaspects of the depot 100 overtime. Such mechanical aspects includestructural integrity, flexural strength, tensile strength, or othermechanical characteristics of the depot 100. In some instances,undesirable degradation of the depot 100, such as premature degradation,can cause mechanical failure of the depot 100 and a correspondingundesirable burst release of therapeutic agent into the body.Accordingly, it can be beneficial for the depot 100 to maintainsufficient flexural strength and/or mechanical integrity in vivo for atleast a predetermined period of time or until a predetermined proportionof therapeutic agent has been released from the depot 100. The depot 100can be considered to maintain its structural integrity if the depot 100remains largely intact with only partial or gradual reduction due toelution of therapeutic agent or dissolution of the control layers orreleasing agent. The depot 100 can be considered to lose its structuralintegrity if it separates (e.g., fractures) into multiple componentpieces, for example, with two or more of the resulting pieces being atleast 5% of the previous size of the depot 100. Alternatively, oradditionally, the depot 100 can be considered to lose its structuralintegrity if the release rate of the therapeutic agent increases by morethan a factor of three as compared to the release rate of therapeuticagent in a control depot submerged in a buffered solution.

In some embodiments, the depot 100 is configured to maintain itsstructural integrity in vivo for at least a predetermined length oftime. For example, the depot 100 can be configured to maintain itsstructural integrity in vivo for at least 1 day, at least 2 days, atleast 3 days, at least 4 days, at least 5 days, at least 6 days, atleast 7 days, at least 8 days, at least 9 days, at least 10 days, atleast 11 days, at least 12 days, at least 13 days, at least 14 days, atleast 15 days, at least 16 days, at least 17 days, at least 18 days, atleast 19 days, at least 20 days, at least 21 days, at least 22 days, atleast 23 days, at least 24 days, at least 25 days, at least 26 days, atleast 27 days, at least 28 days, at least 29 days, or at least 30 days,at least 40 days, at least 50 days, at least 60 days, at least 70 days,at least 90 days, at least 100 days, at least 200 days, at least 300days, or at least 365 days.

In some embodiments, the depot 100 is configured to maintain itsstructural integrity in vivo until at least a predetermined proportionof therapeutic agent payload has been released from the depot. Forexample, the depot 100 can be configured to maintain its structuralintegrity in vivo until at least 5% by weight of the original payloadhas been released, at least 10% by weight of the original payload hasbeen released, at least 15% by weight of the original payload has beenreleased, at least 20% by weight of the original payload has beenreleased, at least 25% by weight of the original payload has beenreleased, at least 30% by weight of the original payload has beenreleased, at least 35% by weight of the original payload has beenreleased, at least 40% by weight of the original payload has beenreleased, at least 45% by weight of the original payload has beenreleased, at least 50% by weight of the original payload has beenreleased, at least 55% by weight of the original payload has beenreleased, at least 60% by weight of the original payload has beenreleased, at least 65% by weight of the original payload has beenreleased, at least 70% by weight of the original payload has beenreleased, at least 75% by weight of the original payload has beenreleased, at least 80% by weight of the original payload has beenreleased, at least 85% by weight of the original payload has beenreleased, at least 90% by weight of the original payload has beenreleased, or until at least 95% by weight of the original payload hasbeen released.

One aspect of the structural integrity of the depot 100 when it is invivo can be quantified using a bend test, such as a three-point bendtest that measures flexural properties including the flexural strengthand/or maximum flexural stress sustained by a specimen before breaking.Such a bend test may represent (e.g., simulate) the forces that thedepot 100 will encounter in vivo in an anatomical joint (e.g., a kneejoint). In one example, a depot can be subjected to a three-point bendtest based on ASTM-D790-17, “Standard Test Methods for FlexuralProperties of Unreinforced and Reinforced Plastics and ElectricalInsulating Materials.” The text of this standard is hereby incorporatedby reference in its entirety. The depot 100 may be suspended in a mediumconfigured to simulate in vivo conditions, for example a phosphatebuffered saline (PBS) at approximately 37° C. The bend test may beperformed after different time periods of submersion in the medium toevaluate changes in the flexural strength of the depot 100 over time insimulated in vivo conditions.

Table 1 shows the maximum flexural load sustained by four differentsamples of the depot 100 at different time periods following submersionin the medium as measured using a three-point bend test with maximumdeflection set at 2.13 mm. The values in Table 1 reflect measurementsmade from two instances of each of the listed samples. FIG. 15 is agraph illustrating these values plotted graphically and fitted withtrendlines. In each of these four samples, the depot 100 includes atherapeutic region 200 surrounded by upper and lower control regions 300a-b as shown and described above with reference to FIG. 4 or 5. Thetherapeutic region 200 has exposed lateral surfaces 202 between thefirst and second control regions 300 a-b. The depots 100 each havelateral dimensions of approximately 2.5 cm by 1.5 cm, with a thicknessof approximately 1 mm.

Sample 1 is a depot having a therapeutic region with a ratio by weightof releasing agent to polymer to therapeutic agent of 0.5:10:20. Thepolymer in this sample is P(DL)GACL with a PDLLA:PGA:PCL ratio of 6:3:1,the releasing agent is Tween 20, and the therapeutic agent isbupivacaine hydrochloride. In this sample, the depot includes a firstcontrol region 300 a comprising a single control layer over the uppersurface of the therapeutic region 200 and a second control region 300 bcomprising single control layer over the lower surface of thetherapeutic region 200, as shown and described above with reference toFIG. 4. Each control region 300 a-b individually has a ratio ofreleasing agent to polymer of 5:10.

Sample 2 is a depot having a therapeutic region 200 with a ratio byweight of releasing agent to polymer to therapeutic agent of 1:10:20.The polymer in this sample is PLGA with a PLA:PGA ratio of 1:1, thereleasing agent is Tween 20, and the therapeutic agent is bupivacainehydrochloride. Similar to Sample 1, the depot of Sample 2 includes acontrol region 300 comprising a first control region 300 a with a singlecontrol layer over the upper surface of the therapeutic region 200 and asecond control region 300 b comprising a single control layer over thelower surface of the therapeutic region 200, as shown and describedabove with reference to FIG. 4. Each control region 300 a-b individuallyhas a ratio of releasing agent to polymer of 5:10.

Sample 3 is a depot having therapeutic region 200 with a ratio by weightof releasing agent to polymer to therapeutic agent of 5:10:20. Thepolymer in this sample is P(DL)GACL with a PDLLA:PGA:PCL ratio of 6:3:1,the releasing agent is Tween 20, and the therapeutic agent isbupivacaine hydrochloride. In this sample, the depot includes a controlregion 300 comprising a first control region 300 a with two sub-controlregions 302 a-b over the upper surface of the therapeutic region 200,and a second control region 300 b with two sub-control regions 302 c-d,as shown and described above with reference to FIG. 5. Each of the innersub-control regions 302 b and 302 c contacts the surface of thetherapeutic region 200 and has a ratio of releasing agent to polymer of5:10, and each of the outer sub-control regions 302 a and 302 d has aratio of releasing agent to polymer of 1:10. The depot of Sample 3,therefore, includes a total of four sub-control regions.

Sample 4 is a depot having a therapeutic region 200 with a ratio byweight of releasing agent to polymer to therapeutic agent of 5:10:20.The polymer in this sample is PLGA with a PLA:PGA ratio of 1:1, thereleasing agent is Tween 20, and the therapeutic agent is bupivacainehydrochloride. As with Sample 3, the depot of Sample 4 includes acontrol region 300 having first and second control region 300 a-b thateach have two sub-control regions 302 a-b and 302 c-d, respectively, asshown and described with respect to FIG. 5. The depot of Sample 4according also has a total of four sub-control regions 302 a-d, two overthe upper surface of the therapeutic region 200 and two over the lowersurface of the therapeutic region 200. The inner of the sub-controlregions 302 b and 302 c has a ratio of releasing agent to polymer of5:10, and the outer of the sub-control regions 302 a and 302 d has aratio of releasing agent to polymer of 1:10.

TABLE 1 Depot Sample Day 0 Day 1 Day 3 Day 7 Day 14 Day 28 Sample 1: No5.553 N 2.903 N 0.569 N 1.263 N Not P(DL)GACL 6:3:1 break 1.25 lbf0.0653 lbf 0.134 lbf 0.284 lbf tested 2 control layers Sample 2: 5.623 N5.447 N 4.623 N 1.386 N Not Not PLGA 1:1 1.264 lbf 1.22 lbf 1.04 lbf0.312 lbf tested tested 2 control layers Sample 3: No 5.474 N Not 2.430N 0.605 N Sample P(DL)GACL 6:3:1 break 1.23 lbf tested 0.546 lbf 0.136lbf degraded 4 control layers Sample 4: No 6.763 N Not 1.816 N 0.869 NSample PLGA 1:1 break 1.52 lbf tested 0.408 lbf 0.195 lbf degraded 4control layers

As shown in Table 1, all samples were intact and maintained sufficientstructural integrity after 14 days of being suspended in the medium towithstand a bending force before fracturing. Although the maximum loadtolerated by each sample decreased over time, the flexural strength ofthese samples at 14 days was sufficient to maintain the structuralintegrity desired for implantation in an active joint, such as the kneeor shoulder. As shown above, for two of the samples tested at 28 days,the samples had degraded such that the test could not be performedbecause the sample was no longer structurally intact. In such instances,it may be desirable to configure the depots such that all orsubstantially all the therapeutic agent payload has been released fromthe depot prior to its degradation and loss of structural integrity.

In this series of experiments summarized in Table 1, the sample depotsare generally flexible at Day 0 before submersion in PBS. Followingsubmersion, the flexural strength of the depots decreased such that thedepots became more brittle with time. Yet, at 7-14 days, the depots werestill sufficiently functionally intact. Without being bound by theory,it is believed that after the therapeutic agent has eluted, the depotsgradually become an empty polymer matrix. For example, after 14-28 daysin the solution, the depots may weigh only approximately 30% of theirstarting weight before submersion in the PBS. At this lower weight andin the porous state, the depots may be more brittle, with lower flexuralstrength and less resistance to bending loads.

As noted above, it can be advantageous for the depots 100 to maintaintheir structural integrity and flexural strength even while theygradually degrade as the therapeutic agent payload releases into thebody. In some embodiments, the depot 100 can be configured such that, inin vitro testing utilizing a three-point bend test, the flexuralstrength of the depot 100 decreases by no more than 95%, no more than90%, no more than 85%, no more than 80%, no more than 75%, no more than70%, no more than 65%, no more than 60%, no more than 55%, no more than50%, no more than 45%, no more than 40%, no more than 35%, no more than30%, no more than 25%, no more than 20%, no more than 15%, no more than10%, or no more than 5% after being submerged in PBS for a predeterminedperiod of time. In various embodiments, the predetermined period of timethat the depot 100 is submerged in PBS before being subjected to thethree-point bend test is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days,7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15days, 16 days, 17 days, 18 days, 19 days, 20 days, after 21 days, after22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, or more.In at least some embodiments, the change in flexural strength of thedepot 100 can be measured between day 0 (e.g., before submersion in thePBS) and a subsequent time after some period of submersion in PBS. Inother embodiments, the change in flexural strength of the depot 100 canbe measured between day 1 (e.g., after 24 hours of submersion in PBS)and a subsequent time following longer submersion in PBS.

In some embodiments, the depot 100 can be configured such that, in invitro testing utilizing a three-point bend test, the flexural strengthof the depot 100 decreases by no more than 95%, no more than 90%, nomore than 85%, no more than 80%, no more than 75%, no more than 70%, nomore than 65%, no more than 60%, no more than 55%, no more than 50%, nomore than 45%, no more than 40%, no more than 35%, no more than 30%, nomore than 25%, no more than 20%, no more than 15%, no more than 10%, orno more than 5% over the time period in which a predetermined percentageof the initial therapeutic agent payload is released while the depot 100is submerged in PBS. In various embodiments, the predeterminedpercentage of payload released when the depot 100 is submerged in PBSbefore being subjected to the three-point bend test is about 5%, about10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%,about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about t 85%, about 90%, or about 95%. As noted above, inat least some embodiments, the change in flexural strength of the depot100 can be measured between day 0 (prior to submersion in PBS) or day 1(after 24 hours of submersion in PBS) and a subsequent following longersubmersion in PBS.

In some embodiments, the depot 100 has (a) lateral dimensions of about1.0-3.0 cm, (b) a thickness of about 0.5-2.5 mm, and (c) a payload oftherapeutic agent sufficient to release about 100 mg to about 500 mg oftherapeutic agent per day for up to 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, or 20 days, and the depot 100 is configured to remainsufficiently mechanically intact to provide sustained, controlledrelease of therapeutic agent for at least 7 days. Such embodiments ofthe depot 100 can comprise the therapeutic region 200 with a therapeuticagent and the control region 300. The control region 300 can have firstand second control regions 300 a-b, such as those shown and describedabove with reference to FIGS. 4-13, and the control region 300 comprisesa bioresorbable polymer and a releasing agent mixed with thebioresorbable polymer. The releasing agent is configured to dissolvewhen the depot 100 is placed in vivo to form diffusion openings in thecontrol region 300. The depot 100 is further configured such that,following submersion of the depot 100 in a buffer solution for sevendays, the flexural strength of the depot 100 decreases by no more than75%, or by no more than 70%, or by no more than 65%, or by no more than60%, or by no more than 55%, or by no more than 50%, or by no more than45%

In some embodiments, the depot 100 has (a) lateral dimensions of about1.0-3.0 cm, (b) a thickness of about 0.5-2.5 mm, and (c) a payload oftherapeutic agent sufficient to release about 100 mg to about 500 mg oftherapeutic agent per day for up to 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, or 20 days, and the depot 100 is configured to remainsufficiently mechanically intact to provide sustained, controlledrelease of therapeutic agent for at least 7 days. Such embodiments ofthe depot 100 can comprise the therapeutic region 200 with a therapeuticagent and the control region 300. The control region 300 can have firstand second control regions 300 a-b, such as those shown and describedabove with reference to FIGS. 4-13, and the control region 300 comprisesa bioresorbable polymer and a releasing agent mixed with thebioresorbable polymer. The releasing agent is configured to dissolvewhen the depot 100 is placed in vivo to form diffusion openings in thecontrol region 300. The depot is further configured such that, followingsubmersion of the depot in buffer solution until approximately 75% ofthe therapeutic agent by weight has been released, the flexural strengthof the depot decreases by no more than 75%, or by no more than 70%, orby no more than 65%, or by no more than 60%, or by no more than 55%, orby no more than 50%, or by no more than 45%.

A. Therapeutic Region

The total payload and release kinetics of the depots 100 of the presenttechnology may be tuned for a particular application by varying thecomposition of the therapeutic region 200. In many embodiments, thetherapeutic region 200 may include a high therapeutic payload of atherapeutic agent, especially as compared to other known polymer devicesof equal thickness or polymer weight percentage. For example, the depots100 of the present technology may comprise at least 15% by weight of thetherapeutic agent, at least 20% by weight of the therapeutic agent, atleast at least 25% by weight of the therapeutic agent, at least 30% byweight of the therapeutic agent, at least 35% by weight of thetherapeutic agent, at least 40% by weight of the therapeutic agent, atleast 45% by weight of the therapeutic agent, at least 50% by weight ofthe therapeutic agent, at least 55% by weight of the therapeutic agent,at least 60% by weight of the therapeutic agent, at least 65% by weightof the therapeutic agent, at least 70% by weight of the therapeuticagent, at least 75% by weight of the therapeutic agent, at least 80% byweight of the therapeutic agent, at least 85% by weight of thetherapeutic agent, at least 90% by weight of the therapeutic agent, atleast 95% by weight of the therapeutic agent, or 100% by weight of thetherapeutic agent.

The therapeutic agent may be any of the therapeutic agents disclosedherein, for example in Section C (“Therapeutic Agents”) below.

In various embodiments of the depots 100 disclosed herein, thetherapeutic region 200 may take several different forms. In someembodiments (for example, FIG. 4), the therapeutic region 200 maycomprise a single layer comprised of a therapeutic agent, a therapeuticagent mixed with a bioresorbable polymer, or a therapeutic agent mixedwith a bioresorbable polymer and a releasing agent. In some embodiments,the therapeutic region 200 itself may comprise a structure havingmultiple layers or sub-regions of therapeutic agent (and/orbioresorbable polymer and/or releasing agent). Some or all layers orsub-regions of such a multiple layer therapeutic region 200 may bedirectly adjacent (i.e., in contact with) one another (laterally oraxially), and/or some or all layers or sub-regions may be spaced apartwith one or more other regions therebetween (such as control region(s)300 and/or barrier region(s))). In some embodiments, 2, 3, 4, 5, 6, 7,8, 9, 10 or more therapeutic sub-regions or layers may be groupedtogether and spaced apart from another therapeutic region or group oftherapeutic sub-regions or layers (having the same or different numbersof layers as the other group) with one or more other regionstherebetween (such as control region(s) 300 and/or barrier region(s)))(see, for example, FIG. 5, FIG. 6, etc.).

In any of the depot embodiments disclosed herein, the ratio of the massof the therapeutic agent in the depot to the mass of polymer in thedepot is at least 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1,8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, or 16:1.

In any of the depot embodiments disclosed herein, the ratio of the massof the polymer in the therapeutic region 200 to the mass of therapeuticagent in the therapeutic region 200 is at least 1:1, 1:1.5, 1:2, 1:2.5,1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5,1:9, 1:9.5, or 1:10.

In any of the embodiments disclosed herein, the weight ratio ofreleasing agent to polymer in the therapeutic region 200 may be 1:1,1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13,1:14, 1:15, or 1:16.

In some embodiments, the ratio of releasing agent to polymer totherapeutic agent in the therapeutic region 200 is of from about0.1:10:20 to about 2:10:20, about 0.1:10:20 to about 1:10:20, about0.1:10:20 to about 0.5:10:20, about 0.5:10:20 to about 0.1:10:20, orabout 0.5:10:20 to about 1:10:20.

In any of the embodiments disclosed herein having a single therapeuticregion 200, the therapeutic region 200 may have a thickness of fromabout 5 μm to 100 μm, 5 μm to 50 μm, 5 μm to 25 μm, 5 μm to 10 μm, 5 μmto 7 μm, 7 μm to 9 μm, 10 μm to 80 μm, 10 μm to 70 μm, 10 μm to 60 μm,20 μm to 60 μm, 15 μm to 50 μm, about 15 μm, about 20 μm, about 25 μm,about 30 μm, about 35 μm, about 40 μm, about 45 μm, about 50 μm, about55 μm, about 60 μm, about 65 μm, about 70 μm, about 75 μm, about 80 μm,about 85 μm, about 90 μm, about 95 μm, about 100 μm, 100 μm to 2 mm, 100μm to 1.5 mm, 100 μm to 1 mm, 100 μm to 200 μm, 200 μm to 300 μm, 300 μmto 400 μm, 400 μm to 500 μm, 500 μm to 600 μm, 600 μm to 700 μm, 700 μmto 800 μm, 800 μm to 900 μm, 900 μm to 1 mm, 1 mm to 1.5 mm, 200 μm to600 μm, 400 μm to 1 mm, 500 μm to 1.1 mm, 800 μm to 1.1 mm, about 200μm, about 300 μm, about 400 μm, about 500 μm, about 600 μm, about 700μm, about 800 μm, about 900 μm, about 1 mm, about 1.1 mm, about 1.2 mm,about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm,about 1.8 mm, about 1.9 mm, or about 2 mm.

In those embodiments having multiple therapeutic regions and/orsub-regions, the individual sub-regions or combinations of some or allsub-regions may have a thickness of from about 5 μm to 100 μm, 5 μm to50 μm, 5 μm to 25 μm, 5 μm to 10 μm, 5 μm to 7 μm, 7 μm to 9 μm, 10 μmto 80 μm, 10 μm to 70 μm, 10 μm to 60 μm, 20 μm to 60 μm, 15 μm to 50μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 35 μm,about 40 μm, about 45 μm, about 50 μm, about 55 μm, about 60 μm, about65 μm, about 70 μm, about 75 μm, about 80 μm, about 85 μm, about 90 μm,about 95 μm, about 100 μm, 100 μm to 2 mm, 100 μm to 1.5 mm, 100 μm to 1mm, 100 μm to 200 μm, 200 μm to 300 μm, 300 μm to 400 μm, 400 μm to 500μm, 500 μm to 600 μm, 600 μm to 700 μm, 700 μm to 800 μm, 800 μm to 900μm, 900 μm to 1 mm, 1 mm to 1.5 mm, 200 μm to 600 μm, 400 μm to 1 mm,500 μm to 1.1 mm, 800 μm to 1.1 mm, about 200 μm, about 300 μm, about400 μm, about 500 μm, about 600 μm, about 700 μm, about 800 μm, about900 μm, about 1 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9mm, or about 2 mm.

The therapeutic regions 200 of the present technology may comprise atleast 15% by weight of the therapeutic agent, at least 20% by weight ofthe therapeutic agent, at least at least 25% by weight of thetherapeutic agent, at least 30% by weight of the therapeutic agent, atleast 35% by weight of the therapeutic agent, at least 40% by weight ofthe therapeutic agent, at least 45% by weight of the therapeutic agent,at least 50% by weight of the therapeutic agent, at least 55% by weightof the therapeutic agent, at least 60% by weight of the therapeuticagent, at least 65% by weight of the therapeutic agent, at least 70% byweight of the therapeutic agent, at least 75% by weight of thetherapeutic agent, at least 80% by weight of the therapeutic agent, atleast 85% by weight of the therapeutic agent, at least 90% by weight ofthe therapeutic agent, at least 95% by weight of the therapeutic agent,or 100% by weight of the therapeutic agent.

In any of the embodiments disclosed herein, the therapeutic region 200may include of from about 0.1%-10% by weight of the releasing agent,about 0.1%-6% by weight of the releasing agent, 0.2%-10% by weight ofthe releasing agent, about 0.3%-6% by weight of the releasing agent,about 0.1%-1% by weight of the releasing agent, about 0.1%-0.5% byweight of the releasing agent, 1%-2% by weight of the releasing agent,about 1%-3% by weight of the releasing agent, or about 2%-6% by weightof the releasing agent. In those embodiments having multiple therapeuticregions or sub-regions, one or more of the therapeutic regions orsub-therapeutic regions may individually include of from about 0.1%-10%by weight of the releasing agent, about 0.1%-6% by weight of thereleasing agent, 0.2%-10% by weight of the releasing agent, about0.3%-6% by weight of the releasing agent, about 0.1%-1% by weight of thereleasing agent, about 0.1%-0.5% by weight of the releasing agent, 1%-2%by weight of the releasing agent, about 1%-3% by weight of the releasingagent, or about 2%-6% by weight of the releasing agent. The therapeuticregion 200 may not include any releasing agent. In those embodimentshaving multiple therapeutic regions and/or sub-regions, one, some, orall of the individual therapeutic regions and/or sub-regions may notinclude any releasing agent.

In any of the embodiments disclosed herein, the therapeutic region 200may include no more than 5% by weight of the polymer, no more than 10%by weight of the polymer, no more than 15% by weight of the polymer, nomore than 20% by weight of the polymer, no more than 25% by weight ofthe polymer, no more than 30% by weight of the polymer, no more than 35%by weight of the polymer, no more than 40% by weight of the polymer, nomore than 45% by weight of the polymer, or no more than 50% by weight ofthe polymer. In those embodiments having multiple therapeutic regions orsub-regions, one or more of the therapeutic regions or sub-therapeuticregions may individually include no more than 5% by weight of thepolymer, no more than 10% by weight of the polymer, no more than 15% byweight of the polymer, no more than 20% by weight of the polymer, nomore than 25% by weight of the polymer, no more than 30% by weight ofthe polymer, no more than 35% by weight of the polymer, no more than 40%by weight of the polymer, no more than 45% by weight of the polymer, orno more than 50% by weight of the polymer. In some embodiments, thetherapeutic region 200 may not include any polymer.

In those embodiments disclosed herein where the therapeutic region 200includes multiple therapeutic regions or sub-regions, some or all of thetherapeutic regions or sub-therapeutic regions may have the same ordifferent amounts of releasing agent, the same or differentconcentrations of releasing agent, the same or different releasingagents, the same or different amounts of polymer, the same or differentpolymers, the same or different polymer to releasing agent ratios, thesame or different amounts of therapeutic agents, the same or differenttypes of therapeutic agents, and/or the same or different thicknesses.Moreover, a single therapeutic region or sub-region may comprise asingle type of polymer or multiple types of polymers, a single type ofreleasing agent or multiple types of releasing agents, and/or a singletype of therapeutic agent or multiple types of therapeutic agents. Inthose embodiments having multiple therapeutic regions and/orsub-regions, one, some, or all of the individual therapeutic regionsand/or sub-regions may not include any polymer.

In some embodiments the therapeutic region 200 (or one or moretherapeutic sub-regions) comprises the therapeutic agent as anessentially pure compound or formulated with a pharmaceuticallyacceptable carrier such as diluents, adjuvants, excipients or vehiclesknown to one skilled in the art

B. Control Region

The composition of the control region 300 may also be varied. Forexample, in many embodiments, the control region 300 does not includeany therapeutic agent at least prior to implantation of the depot at thetreatment site. In some embodiments, the control region 300 may includea therapeutic agent which may be the same as or different than thetherapeutic agent in the therapeutic region 200.

Within the control region 300, the amount of releasing agent may bevaried to achieve a faster or slower release of the therapeutic agent.In those embodiments where both the therapeutic region 200 and controlregion 300 include a releasing agent, the type of releasing agent withinthe therapeutic region 200 may be the same or different as the releasingagent in the control region 300. In some embodiments, a concentration ofa first releasing agent within the control region is the greater than aconcentration of a second releasing agent (the same or different as thefirst releasing agent) within the therapeutic region. In someembodiments, a concentration of the releasing agent within the controlregion is less than a concentration of the releasing agent within thetherapeutic region. In some embodiments, a concentration of thereleasing agent within the control region 300 is the same as aconcentration of the releasing agent within the therapeutic region 200.

In various embodiments of the depots disclosed herein, the controlregion 300 may take several different forms. In some embodiments (forexample, FIG. 4), the control region 300 may comprise a single layer oneither side of the therapeutic region 200 comprised of a bioresorbablepolymer mixed with a releasing agent. In some embodiments, the controlregion 300 itself may comprise a structure having multiple layers orsub-regions of bioresorbable polymer and releasing agent. Some or alllayers or sub-regions of such a multiple layer control region 300 may bedirectly adjacent (i.e., in contact with) one another (laterally oraxially), and/or some or all layers or sub-regions may be spaced apartwith one or more other regions therebetween (such as therapeuticregion(s) 200 and/or barrier region(s))). In some embodiments, 2, 3, 4,5, 6, 7, 8, 9, 10 or more control sub-regions or layers may be groupedtogether and spaced apart from another control region or group ofcontrol sub-regions or layers (having the same or different numbers oflayers as the other group) with one or more other regions therebetween(such as therapeutic region(s) 200 and/or barrier region(s))) (see, forexample, FIG. 5, FIG. 6, etc.).

Without being bound by theory, it is believed that such a multilayerconfiguration improves the control region's ability to control therelease of the therapeutic agent as compared to a single layer controlregion, even if the multilayer configuration has the same or lowerthickness as the single layer control region. The channels left bydissolution of the releasing agent in both microlayers and/orsub-regions of the control region create a path for a releasedtherapeutic agent to travel that is longer and, potentially, morecumbersome to traverse as compared to the more direct path created bythe channels in the single layer control region. The control region(s)and/or sub-regions thereby regulate the therapeutic agent release rateby allowing a releasing agent to form independent non-contiguouschannels through one or more control regions and/or sub-regions. Inthose embodiments having multiple control layers or sub-regions, some orall of the control layers or sub-regions may be heat compressedtogether. The one or more control regions, heat-compressed first or not,may be heat compressed together with the therapeutic region 200. Havinga control region 300 with multiple layers may provide a more linear,controlled release of the therapeutic agent over time (beyond the firstday of implantation). In addition, layering of the control region 300may also contribute to a more flexible, structurally competent depot (ascompared to a depot having a therapeutic region comprised of puretherapeutic agent). Such durability is beneficial for the clinician whenhandling/manipulating the depot 100 before and while positioning thedepot 100 at a treatment site.

In any of the embodiments disclosed herein having a single controlregion 300, the thickness of the control region 300 may be of from about5 μm to 100 μm, 5 μm to 50 μm, 5 μm to 25 μm, 5 μm to 10 μm, 5 μm to 7μm, 7 μm to 9 μm, 10 μm to 80 μm, 10 μm to 70 μm, 10 μm to 60 μm, 20 μmto 60 μm, 15 μm to 50 μm, about 15 μm, about 20 μm, about 25 μm, about30 μm, about 35 μm, about 40 μm, about 45 μm, about 50 μm, about 55 μm,about 60 μm, about 65 μm, about 70 μm, about 75 μm, about 80 μm, about85 μm, about 90 μm, about 95 μm, or about 100 μm. In those embodimentshaving multiple control regions and/or sub-regions, the individualsub-regions or combinations of some or all sub-regions may have athickness of from about 5 μm to 100 μm, 5 μm to 50 μm, 5 μm to 25 μm, 5μm to 10 μm, 5 μm to 7 μm, 7 μm to 9 μm, 10 μm to 80 μm, 10 μm to 70 μm,10 μm to 60 μm, 20 μm to 60 μm, 15 μm to 50 μm, about 15 μm, about 20μm, about 25 μm, about 30 μm, about 35 μm, about 40 μm, about 45 μm,about 50 μm, about 55 μm, about 60 μm, about 65 μm, about 70 μm, about75 μm, about 80 μm, about 85 μm, about 90 μm, about 95 μm, or about 100μm.

In any of the embodiments disclosed herein, the weight ratio ofreleasing agent to polymer in the control region 300 may be 2:1, 1.5:1,1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12,1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24,or 1:25.

In any of the embodiments disclosed herein, the control region 300 mayinclude at least 5% by weight of the releasing agent, at least 10% byweight of the releasing agent, at least 15% by weight of the releasingagent, at least 20% by weight of the releasing agent, at least 25% byweight of the releasing agent, at least 30% by weight of the releasingagent, at least 35% by weight of the releasing agent, at least 40% byweight of the releasing agent, at least 45% by weight of the releasingagent, or at least 50% by weight of the releasing agent. In thoseembodiments having multiple control regions or sub-regions, one or moreof the control regions or sub-control regions may individually includeat least 5% by weight of the releasing agent, at least 10% by weight ofthe releasing agent, at least 15% by weight of the releasing agent, atleast 20% by weight of the releasing agent, at least 25% by weight ofthe releasing agent, at least 30% by weight of the releasing agent, atleast 35% by weight of the releasing agent, at least 40% by weight ofthe releasing agent, at least 45% by weight of the releasing agent, orat least 50% by weight of the releasing agent.

In any of the embodiments disclosed herein, the control region 300 mayinclude at least 5% by weight of the polymer, at least 10% by weight ofthe polymer, at least 15% by weight of the polymer, at least 20% byweight of the polymer, at least 25% by weight of the polymer, at least30% by weight of the polymer, at least 35% by weight of the polymer, atleast 40% by weight of the polymer, at least 45% by weight of thepolymer, at least 50% by weight of the polymer, at least 55% by weightof the polymer, at least 60% by weight of the polymer, at least 65% byweight of the polymer, at least 70% by weight of the polymer, at least75% by weight of the polymer, at least 80% by weight of the polymer, atleast 85% by weight of the polymer, at least 90% by weight of thepolymer, at least 95% by weight of the polymer, or 100% by weight of thepolymer. In those embodiments having multiple control regions orsub-regions, one or more of the control regions or sub-control regionsmay individually include at least 5% by weight of the polymer, at least10% by weight of the polymer, at least 15% by weight of the polymer, atleast 20% by weight of the polymer, at least 25% by weight of thepolymer, at least 30% by weight of the polymer, at least 35% by weightof the polymer, at least 40% by weight of the polymer, at least 45% byweight of the polymer, at least 50% by weight of the polymer, at least55% by weight of the polymer, at least 60% by weight of the polymer, atleast 65% by weight of the polymer, at least 70% by weight of thepolymer, at least 75% by weight of the polymer, at least 80% by weightof the polymer, at least 85% by weight of the polymer, at least 90% byweight of the polymer, at least 95% by weight of the polymer, or 100% byweight of the polymer.

In those embodiments disclosed herein where the control region 300includes multiple control regions or sub-regions, some or all of thecontrol regions or sub-control regions may have the same or differentamounts of releasing agent, the same or different concentrations ofreleasing agent, the same or different releasing agents, the same ordifferent amounts of polymer, the same or different polymers, the sameor different polymer to releasing agent ratios, and/or the same ordifferent thicknesses. A single control region or sub-region maycomprise a single type of polymer or multiple types of polymers and/or asingle type of releasing agent or multiple types of releasing agents.

C. Therapeutic Agents

The therapeutic agent carried by the depots 100 of the presenttechnology may be any biologically active substance (or combination ofsubstances) that provides a therapeutic effect in a patient in needthereof. As used herein, “therapeutic agent” or “drug” may refer to asingle therapeutic agent, or may refer to a combination of therapeuticagents. In some embodiments, the therapeutic agent may include only asingle therapeutic agent, and in some embodiments, the therapeutic agentmay include two or more therapeutic agents for simultaneous orsequential release.

In several embodiments, the therapeutic agent includes an analgesicagent. The term “analgesic agent” or “analgesic” includes one or morelocal or systemic anesthetic agents that are administered to reduce,prevent, alleviate or remove pain entirely. The analgesic agent maycomprise a systemic and/or local anesthetic, narcotics, and/oranti-inflammatory agents. The analgesic agent may comprise thepharmacologically active drug or a pharmaceutically acceptable saltthereof. Suitable local anesthetics include, but are not limited to,bupivacaine, ropivacaine, mepivacaine, etidocaine, levobupivacaine,trimecaine, carticaine, articaine, lidocaine, prilocaine, benzocaine,procaine, tetracaine, chloroprocaine, and combinations thereof.Preferred local anesthetics include bupivacaine, lidocaine, andropivacaine. Typically, local anesthetics produce anesthesia byinhibiting excitation of nerve endings or by blocking conduction inperipheral nerves. Such inhibition is achieved by anesthetics reversiblybinding to and inactivating sodium channels. Sodium influx through thesechannels is necessary for the depolarization of nerve cell membranes andsubsequent propagation of impulses along the course of the nerve. When anerve loses depolarization and capacity to propagate an impulse, theindividual loses sensation in the area supplied by the nerve. Anychemical compound possessing such anesthetic properties is suitable foruse in the present technology.

In some embodiments, the analgesic may comprise dexamethasone. In someembodiments, the therapeutic agent may comprise a first analgesic and asecond analgesic. In some of such embodiments, one of the first orsecond analgesic is dexamethasone. Dexamethasone may also act as ananti-inflammatory agent.

In some embodiments, the analgesic may comprise tetrodotoxin. In someembodiments, the therapeutic agent may comprise a first analgesic and asecond analgesic. In some of such embodiments, one of the first orsecond analgesic is tetrodotoxin.

In some embodiments, the analgesic may comprise saxitoxin. In someembodiments, the therapeutic agent may comprise a first analgesic and asecond analgesic. In some of such embodiments, one of the first orsecond analgesic is saxitoxin.

In some embodiments, the therapeutic agent includes narcotics, forexample, cocaine, and anti-inflammatory agents. Examples of appropriateanti-inflammatory agents include steroids, such as prednisone,betamethasone, cortisone, dexamethasone, hydrocortisone, andmethylprednisolone. Other appropriate anti-inflammatory agents includenon-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin,Ibuprofen, naproxen sodium, diclofenac, diclofenac-misoprostol,celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac,diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac,fenoprofen, flurbiprofen, ketorolac, meclofenamate, mefenamic acid, andother COX-2 inhibitors, and combinations thereof.

In some embodiments, the therapeutic agent comprises an antibiotic, anantimicrobial or antifungal agent or combinations thereof. For example,suitable antibiotics and antimicrobials include, but are not limited to,amoxicillin, amoxicillin/clavulanate, cephalexin, ciprofloxacin,clindamycin, metronidazole, azithromycin, levofloxacin,sulfamethoxazole/trimethoprim, tetracycline(s), minocycline,tigecycline, doxycycline, rifampin, triclosan, chlorhexidine,penicillin(s), aminoglycides, quinolones, fluoroquinolones, vancomycin,gentamycin, cephalosporin(s), carbapenems, imipenem, ertapenem,antimicrobial peptides, cecropin-mellitin, magainin, dermaseptin,cathelicidin, α-defensins, and α-protegrins. Antifungal agents include,but are not limited to, ketoconazole, clortrimazole, miconazole,econazole, intraconazole, fluconazole, bifoconazole, terconazole,butaconazole, tioconazole, oxiconazole, sulconazole, saperconazole,voriconazole, terbinafine, amorolfine, naftifine, griseofulvin,haloprogin, butenafine, tolnaftate, nystatin, cyclohexamide, ciclopirox,flucytosine, terbinafine, and amphotericin B.

The depot of any one of the preceding clauses, wherein the analgesic isa local anesthetic, and wherein the release of the analgesic to thetreatment site over the five days inhibits the growth of bacteria andfungi.

In some embodiments, the therapeutic agent is a local anesthetic andrelease of the anesthetic to the treatment site over the duration ofdelivery inhibits the growth of bacteria and fungi. In some embodiments,the depot is configured to inhibit the growth of bacteria and fungi suchthat a number of bacteria on the depot is 10×, 20×, 30×, 40×, or 50×less than a number of bacteria present on a comparable depot containingno analgesic.

In several embodiments, the therapeutic agent may be anadrenocorticostatic, a β-adrenolytic, an androgen or antiandrogen, anantianemic, a antiparasitic, an anabolic, an anesthetic or analgesic, ananaleptic, an antiallergic, an antiarrhythmic, an anti-arteriosclerotic,an antibiotic, an antidiabetic, an antifibrinolytic, an anticonvulsive,an angiogenesis inhibitor, an anticholinergic, an enzyme, a coenzyme ora corresponding inhibitor, an antihistaminic, an antihypertensive, anantihypotensive, an anticoagulant, an antimycotic, an antiseptic, ananti-infective, an antihemorrhagic, a β-receptor antagonist, a calciumchannel antagonist, an antimyasthenic, an antiphlogistic, anantipyretic, an antirheumatic, a cardiotonic, a chemotherapeutic, acoronary dilator, a cytostatic, a glucocorticoid, a hemostatic, animmunoglobulin or its fragment, a chemokine, a cytokine, a mitogen, acell differentiation factor, a cytotoxic agent, a hormone, animmunosuppressant, an immunostimulant, a morphine antagonist, an musclerelaxant, a narcotic, a vector, a peptide, a (para)sympathicomimetic, a(para)sympatholytic, a protein, a cell, a selective estrogen receptormodulator (SERM), a sedating agent, an antispasmodic, a substance thatinhibits the resorption of bone, a vasoconstrictor or vasodilator, avirustatic or a wound-healing agent.

In various embodiments, the therapeutic agent comprises a drug used inthe treatment of cancer or a pharmaceutically acceptable salt thereof.Such chemotherapeutic agents include antibodies, alkylating agents,angiogenesis inhibitors, antimetabolites, DNA cleavers, DNAcrosslinkers, DNA intercalators, DNA minor groove binders, enediynes,heat shock protein 90 inhibitors, histone deacetylase inhibitors,immunomodulators, microtubule stabilizers, nucleoside (purine orpyrimidine) analogs, nuclear export inhibitors, proteasome inhibitors,topoisomerase (I or II) inhibitors, tyrosine kinase inhibitors, andserine/threonine kinase inhibitors. Specific therapeutic agents include,but are not limited to, adalimumab, ansamitocin P3, auristatin,bendamustine, bevacizumab, bicalutamide, bleomycin, bortezomib,busulfan, callistatin A, camptothecin, capecitabine, carboplatin,carmustine, cetuximab, cisplatin, cladribin, cytarabin, cryptophycins,dacarbazine, dasatinib, daunorubicin, docetaxel, doxorubicin,duocarmycin, dynemycin A, epothilones, etoposide, floxuridine,fludarabine, 5-fluorouracil, gefitinib, gemcitabine, ipilimumab,hydroxyurea, imatinib, infliximab, interferons, interleukins,beta-lapachone, lenalidomide, irinotecan, maytansine, mechlorethamine,melphalan, 6-mercaptopurine, methotrexate, mitomycin C, nilotinib,oxaliplatin, paclitaxel, procarbazine, suberoylanilide hydroxamic acid(SAHA), 6-thioguanidine, thiotepa, teniposide, topotecan, trastuzumab,trichostatin A, vinblastine, vincristine, vindesine, and tamoxifen.

In some embodiments, the therapeutic agent comprises a botulinum toxin(or neurotoxin) drug used in the treatment of various neuromuscularand/or neuroglandular disorders and neuropathies associated with pain.The botulinum toxin (or neurotoxin) may comprise the pharmacologicallyactive drug or a pharmaceutically acceptable salt thereof. The botulinumtoxin (or neurotoxin) as described and used herein may be selected froma variety of strains of Clostridium botulinum and may comprise thepharmacologically active drug or a pharmaceutically acceptable saltthereof. In one embodiment, the botulinum toxin is selected from thegroup consisting of botulinum toxin types A, B, C, D, E, F and G. In apreferred embodiment, the botulinum toxin is botulinum toxin type A.Commercially available botulinum toxin, BOTOX® (Allergan, Inc., Irvine,Calif.), consists of a freeze-dried, purified botulinum toxin type Acomplex, albumin and sodium chloride packaged in sterile, vacuum-driedform.

The paralytic effect of botulinum toxin is the most common benefit ofcommercial therapeutics, where muscles are relaxed in order to treatmuscle dystonias, wrinkles and the like. However, it has been shown thatin addition to its anti-cholinergic effects on muscle and smooth muscle,the neurotoxin can have therapeutic effects on other non-muscular celltypes, and on inflammation itself. For example, it has been shown thatcholinergic goblet cells, which produce mucus throughout the airwaysystem, react to and can be shut down by introduction of botulinumtoxin. Research also shows that botulinum toxin has directanti-inflammatory capabilities. All of these therapeutic effects,muscle, smooth muscle, goblet cell and anti-inflammatory affects, may bederived from delivery of the toxin from the inventive devices.

A pharmaceutically acceptable salt refers to those salts that retain thebiological effectiveness and properties of neutral therapeutic agentsand that are not otherwise unacceptable for pharmaceutical use.Pharmaceutically acceptable salts include salts of acidic or basicgroups, which groups may be present in the therapeutic agents. Thetherapeutic agents used in the present technology that are basic innature are capable of forming a wide variety of salts with variousinorganic and organic acids. Pharmaceutically acceptable acid additionsalts of basic therapeutic agents used in the present technology arethose that form non-toxic acid addition salts, i.e., salts comprisingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, acetate, lactate, salicylate, citrate,tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts. The therapeuticagents of the present technology that include an amino moiety may formpharmaceutically acceptable salts with various amino acids, in additionto the acids mentioned above. Suitable base salts are formed from baseswhich form non-toxic salts and examples are the aluminum, calcium,lithium, magnesium, potassium, sodium, zinc and diethanolamine salts.

A pharmaceutically acceptable salt may involve the inclusion of anothermolecule such as water or another biologically compatible solvent (asolvate), an acetate ion, a succinate ion or other counterion. Thecounterion may be any organic or inorganic moiety that stabilizes thecharge on the parent compound. Furthermore, a pharmaceuticallyacceptable salt may have more than one charged atom in its structure.Instances where multiple charged atoms are part of the pharmaceuticallyacceptable salt can have multiple counter ions. Hence, apharmaceutically acceptable salt can have one or more charged atomsand/or one or more counterion.

The therapeutic agent or pharmaceutically acceptable salt thereof may bean essentially pure compound or be formulated with a pharmaceuticallyacceptable carrier such as diluents, adjuvants, excipients or vehiclesknown to one skilled in the art. The carrier(s) must be “acceptable” inthe sense of being compatible with the other ingredients of theformulations and not deleterious to the recipient thereof. For example,diluents include lactose, dextrose, sucrose, mannitol, sorbitol,cellulose, glycine and the like. For examples of other pharmaceuticallyacceptable carriers, see Remington: THE SCIENCE AND PRACTICE OF PHARMACY(21st Edition, University of the Sciences in Philadelphia, 2005).

The therapeutic agent or pharmaceutically acceptable salt form may bejet milled or otherwise passed through a sieve to form consistentparticle sizes further enabling the regulated and controlled release ofthe therapeutic agent. This process may be particularly helpful forhighly insoluble therapeutic agents.

An important criterion for determining the amount of therapeutic agentneeded for the treatment of a particular medical condition is therelease rate of the drug from the depot of the present technology. Therelease rate is controlled by a variety of factors, including, but notlimited to, the rate that the releasing agent dissolves in vivo into thesurrounding fluid, the in vivo degradation rate of the bioresorbablepolymer or copolymer utilized. For example, the rate of release may becontrolled by the use of multiple control regions between thetherapeutic region and the physiological fluid. See, for example, FIGS.6-8.

Suitable dosage ranges utilizing the depot of the present technology aredependent on the potency of the particular therapeutic agent, but aregenerally about 0.001 mg to about 500 mg of drug per kilogram bodyweight, for example, from about 0.1 mg to about 200 mg of drug perkilogram body weight, and about 1 to about 100 mg/kg-body wt. per day.Dosage ranges may be readily determined by methods known to one skilledin the art. Dosage unit forms will generally contain between about 1 mgto about 500 mg of active ingredient. For example, commerciallyavailable bupivacaine hydrochloride, marketed under the brand nameMarcaine™ (Pfizer; New York, N.Y.), is generally administered as aperipheral nerve block using a dosage range of 37.5-75 mg in a 0.25%concentration and 25 mg up to the daily maximum level (up to 400 mg) ina 0.5% concentration (Marcaine®™ package insert; FDA Reference ID:3079122). In addition, commercially available ropivacaine hydrochloride,marketed under the brand name Naropin® (Fresenius Kabi USA, LLC; LakeZurich, Ill.), is administered in doses of 5-300 mg for minor and majornerve blocks (Naropin® package insert; Reference ID: 451112G). Suitabledosage ranges for the depot of the present technology are equivalent tothe commercially available agents customarily administered by injection.

In some aspects of the technology, the therapeutic region 200 mayinclude multiple layers. In such embodiments, the multiple layers mayimprove efficient loading of therapeutic agents. For example,multilayering may be a direct and effective way of loading substantialamounts of therapeutic agent. It can often be challenging to load alarge amount of therapeutic agent in a single film layer, even byincreasing the drug to polymer ratio or increasing the thickness of thelayer. Even when the thickness of the therapeutic region can betheoretically increased to load more drug, consistent fabrication of athick therapeutic region via casting could prove to be a challenge. Incontrast, the stacking and bonding of thin films or sheets, each with apredetermined load of therapeutic agent, may present as a more reliablecasting alternative. Data from an example of loading an analgesic (i.e.,ropivacaine) is provided in Table 2.

TABLE 2 Drug load Thickness (ug) (mm) Single layer 212.66 0.019 Fivelayers 1120.83 0.046 Multiple 5.27 2.42

As but one example, a single layer loaded with ropivacaine and having athickness of 0.019 mm was produced. A 5-layer film sample, where eachlayer was loaded with ropivacaine, having a thickness of 0.046 mm wasalso produced. Even though the thickness of the 5-layer film sample wasonly 2.42 times the thickness of the single layer, the load oftherapeutic agent in the 5-layer sample was 5.27 times that of thesingle layer sample. Accordingly, the multilayering approach enabled asubstantially higher density of therapeutic agent.

As described above, heat compression bonding of multiple layers enablesan effective reduction in film thickness and an increased density oftherapeutic agent loading. In the example illustrated in Table 2, themultilayer structure enabled a 124% increase in the density of thetherapeutic agent. In other embodiments, the increase in density of thetherapeutic agent enabled by a multilayer structure of the therapeuticregion may be approximately 50%, 75%, 100%, 125%, 150% or 200%.

D. Polymers

The depots 100 of the present technology are comprised of bioresorbablepolymers. In some embodiments, both the therapeutic region 200 and thecontrol region 300 comprise a polymer (or mix of polymers), which can bethe same or different polymer (or mix of polymers) in the same ordifferent amount, concentration, and/or weight percentage. In someembodiments, the control region 300 comprises a polymer and thetherapeutic region 200 does not include a polymer. In some embodiments,the therapeutic region 200 comprises a polymer and the control region300 does not include a polymer. At least as used in this section, “thepolymer” applies to a polymer that may be used in the therapeutic region200 and/or in the control region 300.

The bioresorbable polymers used in the present technology preferablyhave a predetermined degradation rate. The terms “bioresorbable,” or“bioabsorbable,” mean that a polymer will be absorbed within thepatient's body, for example, by a cell or tissue. These polymers are“biodegradable” in that all or parts the polymeric film will degradeover time by the action of enzymes, by hydrolytic action and/or by othersimilar mechanisms in the patient's body. In various embodiments, thebioresorbable polymer film can break down or degrade within the body tonon-toxic components while a therapeutic agent is being released.Polymers used as base components of the depots of the present technologymay break down or degrade after the therapeutic agent is fully released.The bioresorbable polymers are also “bioerodible,” in that they willerode or degrade over time due, at least in part, to contact withsubstances found in the surrounding tissue, fluids or by cellularaction.

Criteria for the selection of the bioresorbable polymer suitable for usein the present technology include: 1) in vivo safety andbiocompatibility; 2) therapeutic agent loading capacity; 3) therapeuticagent releasing capability; 4) degradation profile; 5) potential forinflammatory response; and 6) mechanical properties, which may relate toform factor and manufacturability. As such, selection of thebioresorbable polymer may depend on the clinical objectives of aparticular therapy and may involve trading off between competingobjectives. For example, PGA (polyglycolide) is known to have arelatively fast degradation rate, but it is also fairly brittle.Conversely, polycaprolactone (PCL) has a relatively slow degradationrate and is quite elastic. Copolymerization provides some versatility ifit is clinically desirable to have a mix of properties from multiplepolymers. For biomedical applications, particularly as a bioresorbabledepot for drug release, a polymer or copolymer using at least one ofpoly(L-lactic acid) (PLA), PCL, and PGA are generally preferred. Thephysical properties for some of these polymers are provided in Table 3below.

TABLE 3 Elastic Tensile Tensile Degradation Tg Tm Modulus StrengthElongation Time Materials (° C.) (° C.) (GPa) (MPa) (%) (months) PLA45-60 150-162 0.35-3.5  21-60 2.5-6   12-16  PLLA 55-65 170-200 2.7-1.1415.5-150  3-10 >24 PDLA 50-60 — 1.0-3.45 27.6-50  2-10 6-12 PLA/PGA40-50 — 1.0-4.34 41.4-55.2 2-10  3 (50:50) PGA 35-45 220-233 6.0-7.0  60-99.7 1.5-20  6-12 PCL −60-−65 58-65 0.21-0.44  20.7-42  300-1000 >24

In many embodiments, the polymer may include polyglycolide (PGA). PGA isone of the simplest linear aliphatic polyesters. It is prepared by ringopening polymerization of a cyclic lactone, glycolide. It is highlycrystalline, with a crystallinity of 45-55%, and thus is not soluble inmost organic solvents. It has a high melting point (220-225° C.), and aglass transition temperature of 35-40° C. (Vroman, L., et al.,Materials, 2009, 2:307-44). Rapid in vivo degradation of PGA leads toloss of mechanical strength and a substantial local production ofglycolic acid, which in substantial amounts may provoke an inflammatoryresponse.

In many embodiments, the polymer may include polylactide (PLA). PLA is ahydrophobic polymer because of the presence of methyl (—CH3) side groupsoff the polymer backbone. It is more resistant to hydrolysis than PGAbecause of the steric shielding effect of the methyl side groups. Thetypical glass transition temperature for representative commercial PLAis 63.8° C., the elongation at break is 30.7%, and the tensile strengthis 32.22 MPa (Vroman, 2009). Regulation of the physical properties andbiodegradability of PLA can be achieved by employing a hydroxy acidsco-monomer component or by racemization of D- and L-isomers (Vroman,2009). PLA exists in four forms: poly(L-lactic acid) (PLLA),poly(D-lactic acid) (PDLA), meso-poly(lactic acid) and poly(D,L-lacticacid) (PDLLA), which is a racemic mixture of PLLA and PDLA. PLLA andPDLLA have been the most studied for biomedical applications.

Copolymerization of PLA (both L- and D,L-lactide forms) and PGA yieldspoly(lactide-co-glycolide) (PLGA), which is one of the most commonlyused degradable polymers for biomedical applications. In manyembodiments, the polymer may include PLGA. Since PLA and PGA havesignificantly different properties, careful choice of PLGA compositioncan enable optimization of performance in intended clinicalapplications. Physical property modulation is even more significant forPLGA copolymers. When a composition is comprised of 25-75% lactide, PLGAforms amorphous polymers which are very hydrolytically unstable comparedto the more stable homopolymers. This is demonstrated in the degradationtimes of 50:50 PLGA, 75:25 PLGA, and 85:15 PLGA, which are 1-2 months,4-5 months and 5-6 months, respectively. In some embodiments, thepolymer may be an ester-terminated poly(DL-lactide-co-glycolide) in amolar ratio of 50:50 (DURECT Corporation).

In some embodiments, the polymer may include polycaprolactone (PCL). PCLis a semi-crystalline polyester with high organic solvent solubility, amelting temperature of 55-60° C., and glass transition temperature of−54° C. (Vroman, 2009). PCL has a low in vivo degradation rate and highdrug permeability, thereby making it more suitable as a depot for longerterm drug delivery. For example, Capronor® is a commercial contraceptivePCL product that is able to deliver levonorgestrel in vivo for over ayear. PCL is often blended or copolymerized with other polymers likePLLA, PDLLA, or PLGA. Blending or copolymerization with polyethersexpedites overall polymer erosion. Additionally, PCL has a relativelylow tensile strength (˜23 MPa), but very high elongation at breakage(4700%), making it a very good elastic biomaterial. PCL also is highlyprocessable, which enables many potential form factors and productionefficiencies.

Suitable bioresorbable polymers and copolymers for use in the presenttechnology include, but are not limited to, poly(alpha-hydroxy acids),poly(lactide-co-glycolide)(PLGA or DLG),poly(DL-lactide-co-caprolactone) (DL-PLCL), polycaprolactone (PCL),poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC),polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), polyphosphate ester),poly(amino acid), polydepsipeptides, poly(butylene succinate) (PBS),polyethylene oxide, polypropylene fumarate, polyiminocarbonates,poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone)(PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid,poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide),poly(D,L-lactide-co-glycolide), poly(gycolide-trimethylene carbonate),poly(glycolide-co-carolactone) (PGCL), poly(ethyl glutamate-co-glutamicacid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerolsebacate), tyrosine-derived polycarbonate, poly1,3-bis-(p-carboxyphenoxy) hexane-co-sebacic acid, polyphosphazene,ethyl glycinate polyphosphazene, polycaprolactone co-butylacrylate, acopolymer of polyhydroxybutyrate, a copolymer of maleic anhydride, acopolymer of poly(trimethylene carbonate), polyethylene glycol (PEG),hydroxypropylmethylcellulose and cellulose derivatives, polysaccharides(such as hyaluronic acid, chitosan and starch), proteins (such asgelatin and collagen) or PEG derivatives and copolymers thereof. Othersuitable polymers or copolymers include polyaspirins, polyphosphagenes,collagen, starch, pre-gelatinized starch, hyaluronic acid, chitosans,gelatin, alginates, albumin, fibrin, vitamin E analogs, such as alphatocopheryl acetate, d-alpha tocopheryl succinate, D-lactide,D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL),D,L-lactide-glycolide-caprolactone (DL-G-CL), dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), methacrylates, poly(N-isopropylacrylamide),PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG,PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAM (sucroseacetate isobutyrate)hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose orsalts thereof, Carbopol®, poly(hydroxyethylmethacrylate),poly(methoxyethylmethacrylate), poly(methoxyethoxy-ethylmethacrylate),polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol, or combinations thereof.

In various embodiments, the molecular weight of the polymer can be awide range of values. The average molecular weight of the polymer can befrom about 1000 to about 10,000,000; or about 1,000 to about 1,000,000;or about 5,000 to about 500,000; or about 10,000 to about 100,000; orabout 20,000 to 50,000.

As described above, it may be desirable in certain clinical applicationsusing depots for controlled delivery of therapeutic agents to usecopolymers comprising at least two of PGA, PLA, PCL, PDO, and PVA. Theseinclude, for example, poly(lactide-co-caprolactone) (PLCL) (e.g. havinga PLA to PCL ratio of from 90:10 to 60:40) or its derivatives andcopolymers thereof, poly(DL-lactide-co-caprolactone) (DL-PLCL) (e.g.having a DL-PLA to PCL ratio of from 90:10 to 50:50) or its derivativesand copolymers thereof, poly(glycolide-co-caprolactone) (PGCL) (e.g.having a PGA to PCL ratio of from 90:10 to 10:90) or its derivatives andcopolymers thereof, or a blend of PCL and PLA (e.g. a ratio blend of PCLand PLA having a wt:wt ratio of 1:9 to 9:1). In one preferredembodiment, the bioresorbable polymer comprises a copolymer ofpolycaprolactone (PCL), poly(L-lactic acid) (PLA) and polyglycolide(PGA). In such a preferred embodiment, the ratio of PGA to PLA to PCL ofthe copolymer may be 5-60% PGA, 5-40% PLA and 10-90% PCL. In additionalembodiments, the PGA:PLA:PCL ratio may be 40:40:20, 30:30:50, 20:20:60,15:15:70, 10:10:80, 50:20:30, 50:25:25, 60:20:20, or 60:10:30. In someembodiments, the polymer is an ester-terminatedpoly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio of60:30:10 (DURECT Corporation).

In some embodiments, a terpolymer may be beneficial for increasing thedegradation rate and ease of manufacturing, etc.

To minimize the size of a bioresorbable depot, it is generally preferredto maximize the loading of therapeutic agent in the polymer to achievethe highest possible density of therapeutic agent. However, polymercarriers having high densities of therapeutic agent are more susceptibleto burst release kinetics and, consequently, poor control over timerelease. As described above, one significant benefit of the depotstructure described herein, and particularly the control region featureof the depot, is the ability to control and attenuate the therapeuticagent release kinetics even with therapeutic agent densities that wouldcause instability in other carriers. In certain embodiments, thetherapeutic agent loading capacity includes ratios (wt:wt) of thetherapeutic agent to bioresorbable polymer of approximately 1:3, 1:2,1:1, 3:2, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 14:1, or16:1. In some embodiments, it may be desirable to increase thetherapeutic effect or potency of the therapeutic agent released from thedepot described herein while still maintaining the same or similarpolymer to therapeutic agent ratio. This can be accomplished by using anessentially pure form of the therapeutic agent as opposed to a saltderivative. Additionally or alternatively, the therapeutic agent can bemixed with clonidine or epinephrine, which are known to increase thetherapeutic effect of certain drugs.

In some embodiments, the bioresorbable polymer used in various layers ofthe depot may manifest as a layer of electrospun microfibers ornanofibers. Biocompatible electrospun microfibers/nanofibers are knownin the art and may be used, for example, to manufacture implantablesupports for the formation of replacement organs in vivo (U.S. PatentPublication No. 2014/0272225; Johnson; Nanofiber Solutions, LLC), formusculoskeletal and skin tissue engineering (R. Vasita and D. S. Katti,Int. J. Nanomedicine, 2006, 1:1, 15-30), for dermal or oral applications(PCT Publication No. 2015/189212; Hansen; Dermtreat APS) or formanagement of postoperative pain (U.S. Patent Publication No.2013/0071463; Palasis et al.). As a manufacturing technique,electrospinning offers the opportunity for control over the thicknessand the composition of the nano- or micro-fibers along with control ofthe porosity of the fiber meshes (Vasita and Katti, 2006). Theseelectrospun scaffolds are three-dimensional and thus provide idealsupports for the culture of cells in vivo for tissue formation.Typically, these scaffolds have a porosity of 70-90% (U.S. Pat. No.9,737,632; Johnson; Nanofiber Solutions, LLC). Suitable bioresorbablepolymers and copolymers for the manufacture of electrospun microfibersinclude, but are not limited to, natural materials such as collagen,gelatin, elastin, chitosan, silk fibrion, and hyaluronic acid, as wellas synthetic materials such as poly(ε-caprolactone) (PCL), poly(glycolicacid) (PGA), poly(lactic-co-glycolic acid) (PLGA),poly(l-lactide-co-ε-caprolactone), and poly(lactic acid) (PLA).

Electrospun microfibers that are made from a bioresorbable polymer orcopolymer and have been used in conjunction with a therapeutic agent areknown in the art. For example, Johnson et al. have disclosed thetreatment of joint inflammation and other conditions with an injectionof biocompatible polymeric electrospun fiber fragments along with acarrier medium containing chitosan (U.S. Published Application No.2016/0325015; Nanofiber Solutions, LLC). Weldon et al. reported the useof electrospun bupivacaine-eluting sutures manufactured frompoly(lactic-co-glycolic acid) in a rat skin wound model, wherein thesutures provided local anesthesia at an incision site (J. ControlRelease, 2012, 161:3, 903-909). Similarly, Palasis et al. disclosed thetreatment of postoperative pain by implanting electrospun fibers loadedwith an opioid, anesthetic or a non-opioid analgesic within a surgicalsite (U.S. Patent Publication No. 2013/0071463; Palasis et al.).Electrospun microfibers suitable for use in the present technology maybe obtained by the methods disclosed in the above cited references,which are herein incorporated in their entirety.

When implanted in a patient's joint (for example, a knee joint), thebioresorbable depot described above may be positioned in the joint suchthat it will be articulating throughout the duration of release. So asto avoid premature release of the analgesic, it is desirable for thedepot to have a threshold level of mechanical integrity and stabilityuntil most of the analgesic has been released. While it may be desirableto maximize the loading of therapeutic agent in the bioresorbable depot,as described above, such maximization can typically be at the expense ofmechanical integrity and stability of the depot. Given the high dosageof anesthetic necessary to provide analgesia through both the acute andsubacute postoperative pain periods and limited space in the knee, it isdesirable for the depot described herein to have a high density loadingof anesthetic while still maintaining sufficient mechanical integrityand stability in the knee. The layered structure and, particularly, thepresence of the control region provide some safeguard against thepremature release of anesthetic. Moreover, the use of heat compressionin the manufacturing process enables substantial loading of anestheticinto the therapeutic region while creating a thermal bond between thetherapeutic region and control region, thereby preventing delamination,and a consequent uncontrolled release of drug, when the depot issubjected to mechanical stress in the knee.

It is generally desirable that the implanted polymer fully degradefollowing complete delivery of the therapeutic agent. Full degradationis preferred because, unless the implanted polymer provides somestructural function or support, the clinical practitioner would have toreconcile leaving in a foreign body with no functional purpose, whichcould be a source of inflammation or infection, or perform anothersurgery simply to remove the remaining polymer. As an alternative tofull degradation, it would be desirable for any remaining polymer to befully encapsulated by the body.

The degradation of an implanted polymer consists essentially of twosequential processes: diffusion of an aqueous solution (e.g.,physiological fluids) followed by hydrolytic degradation. Degradationusually takes one of two forms: (1) surface erosion; and (2) bulkdegradation. Surface erosion of a polymer occurs when the polymer erodesfrom the surface inward, where hydrolytic erosion at the surface isfaster than the ingress of water into the polymer. Conversely, bulkdegradation occurs throughout the entire polymer, where water penetratesand degrades the interior of the material faster than the surface canerode. Polymers such as PLA, PGA, PLGA and PCL all resorb into the bodyvia bulk degradation.

The time necessary for complete degradation can vary greatly based onthe material selected and the clinical performance requirements of thedepot. For example, in the case of treating and managing postoperativepain, it may be desirable for the polymer depot to release therapeuticagent (i.e., an analgesic) for anywhere from 5 to 30 days. In the caseof treating or preventing infection of a prosthetic joint (e.g., knee orhip implant), it may be desirable for the polymer depot to release ananti-infective agent for anywhere from 2 to 4 months. Alternatively,even if the entire amount of therapeutic agent loaded into the polymerhas been released, it may be desirable for the polymer to degrade over alonger period than the duration of drug release. For example, rapiddegradation can often make the polymer brittle and fragile, therebycompromising mechanical performance, or provoking an inflammatoryresponse from the body. In particular, it may be desirable, in certainclinical applications, to have an embodiment wherein degradation of thepolymer commenced only after release of substantially all of thetherapeutic agent.

In certain embodiments of the present technology, it may be desirablefor the polymer to fully resorb into the body after substantially alltherapeutic agent loaded therein is released. In certain embodiments,this degradation can be as short as 1 month. Alternatively, in otherembodiments, full degradation could take as long as 2 months, 3 months,4 months, 6 months, 9 months or 12 months. In some embodiments, thebioresorbable polymer substantially degrades in vivo within about onemonth, about two months, about three months, about four months, aboutfive months or about six months. In some embodiments, it may bedesirable for full degradation to be 6 months such that the mechanicalproperties of the implanted polymer are preserved for the first 2 monthsfollowing implantation.

Core Acidification

Traditional bioresorbable implants often lead to tissue inflammation dueto a phenomenon known as “core acidification.” For example, as shownschematically in FIG. 17, polymer implants having a thickness greaterthan 1 mm degrade by bulk erosion (i.e., degradation occurs throughoutthe whole material equally; both the surface and the inside of thematerial degrade at substantially the same time). As the polymerdegrades, lactate accumulates at an internal region of the implant.Eventually, because of the high pH in the internal region of theimplant, the lactate becomes lactic acid. The accumulated lactic acidwill invariably release into the body, thereby provoking an inflammatoryresponse. FIG. 18, for example, is a scanning electron microscope(“SEM”) image of a polymer tablet of the prior art after 20 days ofdegradation. Inflammation in and around a prosthetic joint may beparticularly concerning because of the risk of inflammation-inducedosteolysis, which may cause a loosening of the newly implanted joint.Moreover, core acidification causes extracellular pH to drop, which thencauses the amount of free base bupivacaine to drop. Only free basebupivacaine can cross the lipid bilayer forming the cell membrane intothe neuron. Once bupivacaine crosses into the neuron the percent ofbupivacaine HCl increases. It is the bupivacaine HCl form that is activeby blocking sodium from entering the neuron thus inducing analgesia.Thus, any reduction in extracellular pH (for example, via coreacidification) slows transfer of the analgesic into the neuron, therebyreducing or altogether eliminating the therapeutic effects of theanalgesic.

The degree of core acidification is determined in large part by thegeometry and dimensions of the polymer implant. (See, e.g., Grizzi etal., Hydrolytic degradation of devices based on poly(dl-lactic acid)size-dependence, BIOMATERIALS, 1995, Vol. 16 No. 4, pp. 305-11; Fukuzakiet al., in vivo characteristics of high molecular weightcopoly(l-lactide/glycolide) with S-type degradation pattern forapplication in drug delivery systems, Biomaterials 1991, Vol. 12 May,pp. 433-37; Li et al., Structure-property relationships in the case ofdegradation of massive alipathic poly-(α-hydroxy acids) in aqueousmedia, JOURNAL OF MATERIALS SCIENCE: MATERIALS IN MEDICINE I (1990), pp.123-130.) For example, degradation in more massive monolithic devices(mm-size scales and greater) proceeds much more rapidly in theirinterior than on their surface, leading to an outer layer of slowlydegrading polymer entrapping more advanced internal degradation productsfrom interior zone autocatalysis (so-called “S-type” non-linear kineticdegradation profile.). In contrast to a thicker film, a thin film ofless than 1 mm thickness will typically degrade via surface erosion,wherein the lactate resulting from degradation will not accumulate inthe interior of the film. Thin films, because of their high surface areato volume ratios, are known to degrade uniformly and do not lead to coreacidification. (See Grizzi et al.)

As shown schematically in FIG. 19A, the depots of the present technologymay shed up to 50%, 60%, 70% or 80% of their individual mass (anestheticand releasing agent) over the course of releasing the anesthetic (e.g.,5 days, 7 days, 10 days, 14 days, 20 days, 30 days, etc.), resulting ina highly porous, mesh-like system that at least for the purpose ofdegradation behaves like a thin-film because of its high surface area tovolume ratio. Body fluids will invade the highly porous polymer carrierto degrade the remaining polymer via surface erosion, thereby avoidingcore acidification and the resulting inflammatory response. Withoutbeing bound by theory, it is believed that the drug core matrix of thetherapeutic region becomes highly porous as degradation continues. Forexample, FIGS. 19B and 19C are scanning electron microscope (“SEM”)images showing the therapeutic region before and after elution,respectively. However, even after the release of therapeutic agent,there is still a clear porous structure left through which water andacid can diffuse effectively. Thus, depots 100 of the present technologyhaving a thickness greater than about 1 mm degrade like a thin film, andsurprisingly do not exhibit core acidification.

E. Releasing Agent

In many implantable drug eluting technologies, the depot provides aninitial, uncontrolled burst release of drug followed by a residualrelease. These drug release kinetics may be desirable in certainclinical applications, but may be unavoidable even when undesirable.Hydrophilic drugs loaded in a polymer carrier will typically provide aburst release when exposed to physiologic fluids. This dynamic maypresent challenges, particularly when it is desirable to load a largevolume of drug for controlled, sustained in vivo administration. Forexample, although it may be desirable to implant several days or weeks'worth of dosage to achieve a sustained, durable, in vivo pharmacologicaltreatment, it is imperative that the therapeutic agent is released asprescribed, otherwise release of the entire payload could result insevere complications to the patient.

To achieve finer control over the release of the therapeutic agent whenexposed to fluids, the depots 100 of the present technology may includea releasing agent. In some embodiments, both the therapeutic region 200and the control region 300 include a releasing agent (or mix ofreleasing agents), which can be the same or different releasing agent(or mix of releasing agents) in the same or different amount,concentration, and/or weight percentage. In some embodiments, thecontrol region 300 includes a releasing agent and the therapeutic region200 does not include a releasing agent. In some embodiments, thetherapeutic region 200 includes a releasing agent and the control region300 does not include a releasing agent. At least as used in thissection, “the releasing agent” applies to a releasing agent that may beused in the therapeutic region 200 and/or in the control region 300.

The type and/or amount of releasing agent within the therapeutic region200 and/or control region 300 may be varied according to the desiredrelease rate of the therapeutic agent into the surrounding biologicalfluids. For example, choosing releasing agents with differentdissolution times will affect the rate of release. Also, the weightpercentage of releasing agent in a region of polymer will influence thenumber and the size of the diffusion openings subsequently formed in thepolymer, thereby affecting the rate of therapeutic agent release fromthe depot 100 (e.g., the greater the weight percentage of releasingagent, the faster the release). The presence of releasing agent inselect regions also influences the release rate of therapeutic agent.For example, a depot with releasing agent in the control region 300and/or therapeutic region 200 will generally release therapeutic agentat a higher rate compared to a depot with no releasing agent. Similarly,releasing agent in both the control region 300 and the therapeuticregion 200 will generally release therapeutic agent at a higher ratethan when releasing agent is in the control region alone.

In certain embodiments of the present technology, the layer-by-layerratio of releasing agent to bioresorbable polymer can be adjusted tocontrol the rate of therapeutic agent released from the depot 100. Forexample, in many embodiments of the present technology, the depot 100includes a therapeutic region 200 having a weight percentage ofreleasing agent that is different than the weight percentage of thereleasing agent in the control region 200. For example, the therapeuticregion 200 may have a greater or lesser weight percentage of releasingagent than the control region 300. In some embodiments, the controlregion 300 may have a weight percentage of releasing agent that is atleast 2 times greater than the weight percentage of the releasing agentin the therapeutic region 200. In some embodiments, the control region300 may have a weight percentage of releasing agent that is at least3-20 times greater, at least 4 times greater, at least 5 times greater,at least 6 times greater, at least 7 times greater, at least 8 timesgreater, at least 9 times greater, at least 10 times greater, at least11 times greater, at least 12 times greater, at least 13 times greater,at least 14 times greater, at least 16 times greater, at least 17 timesgreater, at least 18 times greater, at least 19 times greater, at least20 times greater, at least 25 times greater, at least 30 times greater,about 5 to 10 times greater, about 10 to 15 times greater, about 5 to 15times greater, or about 15 to 25 times greater than the weightpercentage of the releasing agent in the therapeutic region 200.

In many embodiments of the present technology, the releasing agent is asurfactant. Unlike the use as a releasing agent as described herein,surfactants are usually used to control the dispersions, flocculationand wetting properties of a drug or polymer. Fundamentally, surfactantsoperate on the interface between the polymer and drug or the interfacebetween the drug and biological membrane. Depending on the type offormulation, surfactants typically play a role in several aspects ofdrug delivery: (1) solubilization or stabilization of hydrophobic drugsby lowering the entropic cost of solvating hydrophobic drug throughcomplexation with drug molecules in solution (C. Bell and K. A. Woodrow,ANTIMICROB. AGENTS CHEMOTHER., 2014, 58:8, 4855-65); (2) improvement ofthe wetting of tablet or polymer for fast disintegration (M. Irfan, etal., SAUDI PHARM. J., 2016, 24, 537-46); (3) formation of colloidal drugdelivery systems, such as reverse micelles, vesicles, liquid crystaldispersions, nanoemulsions and nanoparticles (M. Fanun, Colloids in DrugDelivery, 2010, p. 357); and (4) improvement the bioperformance of drugsby altering the permeability of biological membrane and consequentlydrug penetration/permeation profile (S. Jain, et al., Lipid BasedVesicular Drug Delivery Systems, 2014, Vol. 2014, Article ID 574673).

In order to illustrate the unique aspects of using a releasing agent inthe polymeric control region to form diffusion openings and/ormicrochannels in the present technology, it is helpful to explain themore common approach of using hydrophilic molecules to enhance drugrelease. Conventionally, drug release is enhanced by creating a largersurface area in order to increase contact between the drug and thebodily fluid, thereby accelerating drug release. The most commonmechanism for forming pores prior to implantation is to usenon-surfactant hydrophilic molecules as pore-forming agents in polymerlayers, either as a coating layer or a free-standing film (Kanagale, P.,et al., AAPS PHARM. SCI. TECH., 2007; 8(3), E1-7). Usually, pores arepre-formed by blending hydrophilic molecules with polymer, then removingthe hydrophilic molecules by contact with water. However, whenhydrophilic molecules are blended with hydrophobic polymer, themolecules tend to form hydrophilic domains and hydrophobic domains,which are energetically favorable due to the increase in entropy. Whenthe film contacts water, hydrophilic domains are removed and replacedwith large pores. The rate of drug release in this case is solelycontrolled by the porosity of the film and the resulting increased totalsurface area. The typical drug release curve in this case has a high,uncontrolled initial burst followed with a very slow release of residualdrug afterwards.

Previously, when non-surfactant hydrophilic molecules are mixed into thepolymer and then removed, a film with a porous structure is created.This porous layer reduces mechanical strength and elasticity, making itless suitable for certain applications. Additionally, this structuredoes not withstand heat compression bonding of the film because thepores would collapse. The loss of porous structure during heatcompression negates the original intent of using the hydrophilicmolecule, thus resulting in a densely packed film without any enhancedtherapeutic agent release capability.

Further, if the hydrophilic molecule remains in the polymer layer duringheat compression, the dissolution of the hydrophilic molecule in vivocauses the formation of very large pores, approximately 3-10 μm indiameter. Such large pores provide a large surface area, thereby causinga burst release of drug. In contrast to the use of hydrophilicmolecules, the use of a surfactant as a releasing agent in the presenttechnology enables the formation of microchannels approximately 5-20nanometers in diameter, which is two orders of magnitude smaller thanthe pores resulting from the use of hydrophilic molecules. This allowstight control of the drug release by diffusion and, if desirable,without an uncontrolled burst release upon implantation. Additionally,use of a surfactant as a releasing agent allows the agent to remainpresent in the polymer prior to use and no pre-formed pores are created.This approach is particularly advantageous because the polymer'smechanical properties are preserved, thereby allowing the polymer to beeasily processed and worked into different configurations.

In the present technology, the releasing agent is pre-mixed into thebioresorbable polymer such that each layer of polymer is contiguous anddense. The depot 100 is then formed when these layers are bondedtogether via heat compression without any adverse impact to thefunctional capabilities of the film. When the densely packed film isultimately implanted, the releasing agent dissolves to enable efficient,controlled release of the therapeutic agent.

In some embodiments, the releasing agent comprises a polysorbate.Polysorbate is commonly used in the pharmaceutical industry as anexcipient and solubilizing agent. Polysorbate is a non-ionic surfactantformed by the ethoxylation of sorbitan followed by esterification bylauric acid. Polysorbate 20 [IUPAC name: polyoxyethylene(20)sorbitanmonolaurate] contains a mixture of ethoxylated sorbitan with 20 repeatunits of polyethylene glycol distributed among four different sites inthe sorbitan molecule. Common commercial names include Tween™ and Tween20™ (Croda International Plc, Goole, East Yorkshire, UK) and Alkest® TW20 (Oxiteno, Houston, Tex.).

Polysorbate is often utilized to improve oral bioavailability of apoorly water-soluble/hydrophobic drug. For example, polysorbate was usedto improve bioavailability of active molecules that possess lowsolubility and/or intestinal epithelial permeability and it was observedthat the bioavailability of this poorly water-soluble drug was greatlyenhanced in a formulation with polysorbate or similar surfactants.(WO2008/030425; Breslin; Merck.) Akbari, et al., observed that using thehydrophilic carrier polyethylene glycol (PEG) along with polysorbateleads to faster an oral enhanced drug release rate because thepolysorbate brings the drug in close contact with the PEG. (Akbari, J.,et al., ADV. PHARM. BULL., 2015, 5(3): 435-41.)

Polysorbate also functions as a water-soluble emulsifier that promotesthe formation of oil/water emulsions. For example, the drug famotidineis known to have high solubility in water but low in vivo permeability.Polysorbate was used in an oral microemulsion formulation for enhancingthe bioavailability of famotidine. (Sajal Kumar Jha, et al., IJDDR,2011, 3(4): 336-43.) Polysorbate is also used as a wetting agent toachieve rapid drug delivery. For example, Ball et al., achieved rapiddelivery of maraviroc via a combination of a polyvinylpyrrolidone (PVP)electrospun nanofiber and 2.5 wt % Tween 20, which allowed for thecomplete release of 28 wt % maraviroc in just six minutes. It wasbelieved that use of Tween 20 as a wetting agent allowed water topenetrate the PVP nanofiber matrix more quickly, thereby increasing therate of drug release. (Ball, C., et al., ANTIMICROB. AGENTSCHEMOTHERAPY, 2014, 58:8, 4855-65.)

As described above, in order to improve drug release in certain polymercarriers, hydrophilic polymers, such as polysorbate, have been added tothese carriers to accelerate or to enhance drug release frombiocompatible polymers such as polyethylene glycol (PEG) in oralformulations (Akbari, J., et al., ADV. PHARM. BULL., 2015, 5(3):435-441). However, these formulations are intended to provide animmediate release of a hydrophobic drug into a hydrophilic environment(the in vivo physiologic fluid), not a variable or sustained controlledrelease as part of a control region.

In some embodiments, the releasing agent is polysorbate 20, commerciallyknown as Tween20™. Other releasing agents suitable for use in thepresent technology include polysorbates, such as Polysorbate 80,Polysorbate 60, Polysorbate 40, and Polysorbate 20; sorbitan fatty acidesters, such as sorbitan monostearate (Span 60), sorbitan tristearate(Span 65), sorbitane trioleate (Span 85), sorbitan monooleate (Span 80),sorbitan monopalmitate, sorbitan monostearate, sorbitan monolaurate,sorbitan monopalmitate, sorbitan trioleate, and sorbitan tribehenate;sucrose esters, such as sucrose monodecanoate, sucrose monolaurate,sucrose distearate, and sucrose stearate; castor oils such aspolyethoxylated castor oil, polyoxyl hydrogenated castor oil, polyoxyl35 castor oil, Polyoxyl 40 Hydrogenated castor oil, Polyoxyl 40 castoroil, Cremophor® RH60, and Cremophor® RH40, polyethylene glycol esterglycerides, such as Labrasol®, Labrifil® 1944; poloxamer;polyoxyethylene polyoxypropylene 1800; polyoxyethylene fatty acidesters, such as Polyoxyl 20 Stearyl Ether, diethylene glycol octadecylether, glyceryl monostearate, triglycerol monostearate, Polyoxyl 20stearate, Polyoxyl 40 stearate, polyoxyethylene sorbitanmonoisostearate, polyethylene glycol 40 sorbitan diisostearate; oleicacid; sodium desoxycholate; sodium lauryl sulfate; myristic acid;stearic acid; vitamin E-TPGS (vitamin E d-alpha-tocopherol polyethyleneglycol succinate); saturated polyglycolized glycerides, such asGelucire® 44/14 and and Gelucire® 50/13; and polypropoxylated stearylalcohols such as Acconon® MC-8 and Acconon® CC-6.

Diffusion Openings

The channels or voids formed within the therapeutic region 200 and/orcontrol region 300 by dissolution of the releasing agent may be in theform of a plurality of interconnected openings or pores and/or aplurality of interconnected pathways, referred to herein as “diffusionopenings.” In some embodiments, one or more of the channels may be inthe form of discrete pathways, channels, or openings within therespective therapeutic and/or control region. Depending on the chemicaland material composition of the therapeutic and control regions, one ormore of the formed channels may extend: (a) from a first end within thetherapeutic region to a second end also within the therapeutic region;(b) from a first end within the therapeutic region to a second end atthe interface of the therapeutic region and the control region; (c) froma first end within the therapeutic region to a second end within thecontrol region; (d) from a first end within the therapeutic regionthrough the control region to a second end at an outer surface of thecontrol region; (e) from a first end at the interface between thetherapeutic region and the control region through the control region toa second end within the control region; (f) from a first end at theinterface between the therapeutic region and the control region to asecond end at an outer surface of the control region; (g) from a firstend within the control region to a second end also within the controlregion; and (h) from a first end within the control region to a secondend at an outer surface of the control region. Moreover, one or more ofthe channels may extend between two or more microlayers of thetherapeutic region and/or control region.

F. Constituent Ratios

In some embodiments, the ratio of the polymer in the control region 300to the releasing agent in the control region 300 is at least 1:1. Insome embodiments, the ratio may be at least 1.5:1, at least 2:1, atleast 2.5:1, or at least 3:1.

In some embodiments, a ratio of the mass of the therapeutic agent in thedepot 100 to the polymer mass of the depot is at least 1:1, at least2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least7:1, at least 8:1, at least 9:1, at least 10:1, at least 11:1, at least12:1, at least 13:1, at least 14:1, at least 15:1, or at least 16:1.

In some embodiments, the ratio of releasing agent to polymer totherapeutic agent in the therapeutic region 200 is of from about0.1:10:20 to about 2:10:20, and in some embodiments of from about0.1:10:20 to about 1:10:20, and in some embodiments of from about0.1:10:20 to about 0.5:10:20.

In some embodiments, the ratio of releasing agent to polymer in thecontrol region 300 is of from about 1:2 to about 1:10. In someembodiments, one or more of the control regions may have a ratio ofreleasing agent to polymer of 1:2, and one or more of the other controlregions may have a ratio of releasing agent to polymer of 1:10

G. Selected Depot Embodiments Including a Barrier Region

In some embodiments, the depot 100 may be configured to release thetherapeutic agent in an omnidirectional manner. In other embodiments,the depot may include one or more barrier regions 400 covering one ormore portions of the therapeutic region 200 and/or control region 300,such that release of the therapeutic agent is limited to certaindirections. The barrier region 400 may provide structural support forthe depot. The barrier region 400 may comprise a low porosity, highdensity of bioresorbable polymer configured to provide a directionalrelease capability to the depot. In this configuration, the substantialimpermeability of this low porosity, high density polymer structure inthe barrier region 400 blocks or impedes the passage of agents releasedfrom the therapeutic region 200. Accordingly, the agents released fromthe therapeutic region 200 take a path of less resistance through thecontrol region 300 opposite from the barrier region 400, particularlyfollowing the creation of diffusion openings in the control region 300.

An example a depot 100 of the present technology having a barrier region400 is shown in FIG. 16A. The barrier region 400 may comprise a lowporosity, high density of bioresorbable polymer configured to provide adirectional release capability to the multi-region depot. In thisconfiguration, the low porosity, high density polymer structure in thebarrier region 400 blocks or impedes passage of agents release from thetherapeutic region 200. Accordingly, the agents released from thetherapeutic region 200 take a path of lesser resistance through thecontrol region opposite from the barrier region 400, particularlyfollowing the creation of channels in the control region. In anadditional embodiment, the porosity of other regions of the multi-regiondepot can be varied to facilitate the release of therapeutic agent. Forexample, in this embodiment, the barrier region 400, the therapeuticregion 200, and the control region 300 of the multi-region depotdepicted in FIG. 16A may have different porosities ranging from lowporosity in the barrier region 400 to higher porosities in thetherapeutic agent and control regions to facilitate the release oftherapeutic agent from the multi-region depot. In additionalembodiments, the porosities of the edges of the multi-region depot, orwithin portions of any of the individual regions, can be varied toproperly regulate or manipulate the release of therapeutic agent.

In the embodiment depicted in FIG. 16B, the multi-region depot providesfor a bilateral or bidirectional release of therapeutic agent. Thisbidirectional release capability is accomplished through symmetricregioning about a high-density barrier region 400, wherein, as describedabove, the therapeutic agent releases along a path of less resistance,thereby releasing away from the high density barrier region 400. Morespecifically, disposed on one side of the barrier region 400 is acontrol region 300 a and a therapeutic region 200 a and, disposed on theother side of the barrier region 400, is a control region 300 b and atherapeutic region 200 b that are substantially similar to the pair onthe other side. These pairs on either side of the barrier region 400 areconfigured to produce substantially equivalent, bidirectional release oftherapeutic agent. In an alternate embodiment, a bidirectional releasethat is not equivalent (i.e., the therapeutic agent and/or rate ofrelease in each direction is not the same) may be accomplished byasymmetric regioning, whereby the control region and therapeutic regionpairs on either side of the barrier region 400 are substantiallydifferent.

In additional embodiments, it may be desirable for the multi-regiondepot to release multiple therapeutic agents. This capability can beparticularly useful when multimodal pharmacological therapy isindicated. In the embodiment shown in FIG. 16C, the multi-region depotcomprises a topmost or outermost control region 300 a, a firsttherapeutic region 200 a adjacent to the control region, a secondtherapeutic region 200 b adjacent to the first therapeutic region 200 a,and a barrier region 400 adjacent to the second therapeutic region 200b. In this embodiment, the first therapeutic region 200 a and the secondtherapeutic region 200 b comprise a first therapeutic agent and a secondtherapeutic agent, respectively. In certain embodiments, the first andsecond therapeutic agents are different. In one embodiment, themulti-region depot is configured to release the first and secondtherapeutic agents in sequence, simultaneously, or in an overlappingfashion to yield a complementary or synergistic benefit. In thisconfiguration, the presence and function of the control region 300 a mayalso ensure consistent and, if desired, substantially even release ofmultiple therapeutic agents residing beneath. Since many conventionaldrug delivery devices can fail to provide an even release of multipledrugs with different molecular weights, solubility, etc., the role ofthe control region in achieving a substantially even release ofdifferent therapeutic agents can be a significant advantage.

In some embodiments, the first therapeutic agent and second therapeuticagent are the same therapeutic agent but are present in the first andsecond therapeutic regions, respectively, in different relativeconcentrations to represent different dosages to be administered. Insome embodiments, the first and second therapeutic agents of the firstand second therapeutic regions, respectively, may have no clinicalassociation or relationship whatsoever. For example, in an embodimentfor use as part of a total joint replacement (e.g., total kneearthroplasty, total hip arthroplasty) or other surgical procedure, itmay be clinically desirable to administer in the vicinity of thesurgical site both an analgesic (e.g., local anesthetic) to treat andbetter manage postoperative pain for several days or weeks following thesurgery and an antibiotic to treat or prevent surgical site infectionassociated with the surgery or implanted prosthesis (if any) for severalweeks or months following the surgery. In this embodiment, the firsttherapeutic region 200 a may comprise a therapeutically effective doseof local anesthetic to substantially provide pain relief for no lessthan 3 days and up to 15 days following the surgery and the secondtherapeutic region 200 b may comprise a therapeutically effective doseof antibiotics to substantially provide a minimally effectiveconcentration of antibiotic in the vicinity of the surgical site for upto three months following the surgery.

In some embodiments, as shown in FIG. 16D, the depot 100 comprises afirst dosage region and a second dosage region, wherein the first andsecond dosage regions correspond to first and second dosage regimens.More specifically, each dosage region comprises a control region andtherapeutic region pair, wherein each pair is configured for controlledrelease of a therapeutic agent from the therapeutic region 200 a, 200 bin accordance with a predetermined dosage regimen. For example, intreating and/or managing postoperative pain, it may be desirable for themulti-region depot to consistently release 50-400 mg/day of localanesthetic (e.g., bupivacaine, ropivacaine and the like) for at least2-3 days following surgery (i.e., first dosage regimen) and then releasea local anesthetic at a slower rate (e.g., 25-200 mg/day) for the next 5to 10 days (i.e., second dosage regimen). In this exemplary embodiment,the first dosage region, and the control region and therapeutic regionpair therein, would be sized, dimensioned, and configured such that themulti-region depot releases the first therapeutic agent in a manner thatis consistent with the prescribed first dosage regimen. Similarly, thesecond dosage region, and the control region and therapeutic region pairtherein, would be sized, dimensioned and configured such that themulti-region depot releases the second therapeutic agent in a mannerthat is consistent with the prescribed second dosage regimen. In anotherembodiment, the first and second dosage regions may correspond to dosageregimens utilizing different therapeutic agents. In one embodiment, themulti-region depot 100 is configured to administer the first and seconddosage regimens in sequence, simultaneously, or in an overlappingfashion to yield a complementary or synergistic benefit. In an alternateembodiment of this scenario, the first and second dosage regimens,respectively, may have no clinical association or relationshipwhatsoever. For example, as described above with respect to theembodiment depicted in FIG. 16C, the first dosage regimen administeredvia the first dosage region may be treating or managing postoperativepain management and the second dosage regimen administered via thesecond dosage region may be treating or preventing infection of thesurgical site or implanted prosthesis (if any).

Certain embodiments of the present invention utilize delayed releaseagents. As illustrated in FIG. 16E, the depot 100 may include a barrierregion 400 as the outermost (i.e., topmost) region to the multi-regiondepot and adjacent to a control region 300 comprising a releasing agent.The barrier region 400 presents a barrier to physiologic fluids fromreaching and dissolving the releasing agent within the control region.In one embodiment, the barrier region 400 may comprise a delayed releaseagent mixed with a bioresorbable polymer, but without a releasing agent.Delayed release agents are different from the releasing agents used inthe multi-region depot of the invention. Delayed release agents dissolvein physiological fluids more slowly than do releasing agents and thusprovide the possibility for release of a therapeutic agent a definedamount of time following implantation of the multi-region depot. Inembodiments where a delayed release agent is not present in the barrierregion 400, it may take more time for the physiological fluids totraverse the barrier region 400 and contact the releasing agent. Onlywhen the physiological fluids make contact with the control region willthe releasing agent begin to dissolve, thus allowing the controlledrelease of the therapeutic agent. Delayed release agents may beadvantageously used in the therapeutic methods of the invention whereinthe therapeutic agent is not immediately required. For example, a nerveblocking agent may be injected prior to a surgical procedure, numbingthe entire area around a surgical site. The controlled release of alocal anesthetic is not required in such a surgery until the nerve blockwears off.

Suitable delayed release agents for use in the present invention arepharmaceutically acceptable hydrophobic molecules such as fatty acidesters. Such esters include, but are not limited to, esters ofmyristoleic acid, sapienic acid, vaccenic acid, stearic acid, arachidicacid, palmitic acid, erucic acid, oleic acid, arachidonic acid, linoleicacid, linoelaidic acid, eicosapentaenoic acid, docosahexaenoic acid.Preferred esters include stearic acid methyl ester, oleic acid ethylester, and oleic acid methyl ester. Other suitable delayed releaseagents include tocopherol and esters of tocopherol, such as tocopherylnicotinate and tocopheryl linolate.

H. Additional Depot Configurations

FIGS. 20-36 illustrate various examples of depots 100 having anelongated form. As depicted in FIG. 20, an “elongated depot” or an“elongated form” as used herein refers to a depot configuration in whichthe depot 100 has a length L between its ends along a first axis A1(e.g., a longitudinal axis) that is at least 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, or 30 times greaterthan a maximum dimension D of a cross-sectional slice of the depot 100within a plane orthogonal to the first axis A1. The elongated depots 100described herein may include a therapeutic region 200 containing atherapeutic agent (such as any of the therapeutic agents describedherein) and a control region 300 at least partially surrounding thetherapeutic region 200 to control release of the therapeutic agent fromthe depot 100. The therapeutic region 200 may optionally include abioresorbable polymer (such as any of the polymers described herein)and/or a releasing agent (such as any of the releasing agents describedherein). The control region 300 may include a bioresorbable polymer(such as any of the polymers described herein) mixed with a releasingagent (such as any of the releasing agents described herein), but doesnot include any therapeutic agent at least prior to implantation. Insome embodiments, the control region 300 may include some therapeuticagent prior to implantation, for example having a lower concentration oftherapeutic agent than the therapeutic region 200. As discussed ingreater detail below, the thickness of the control region 300, theconcentration of releasing agent in the control region 300, the amountof exposed (uncovered) surface area of the therapeutic region 200, theshape and size of the depot 100, and other suitable parameters may bevaried to achieve a desired release profile for the sustained,controlled release of the therapeutic agent from the depot 100.

In the embodiments shown in FIGS. 20-36, the elongated depot 100 has acylindrical, columnar, and/or rod-like shape such that thecross-sectional shape is a circle and the cross-sectional dimension D isthe diameter of the circle. In some embodiments, however, the elongateddepot 100 may have another elongated configuration and/orcross-sectional shape along all or a portion of its length L. Forexample, the depot 100 may be in the form of a ribbon-like strip andthus have a square or rectangular cross-sectional shape. In otherembodiments, the elongated depot 100 may have a circular, triangular,rhomboid, or other polygonal or non-polygonal cross-sectional shapebased on the desired application. The elongated depot 100 may be a solidor semi-solid formulation with sufficient column strength to be pushedor pulled from a delivery device and sufficient durability and/orstructural integrity to maintain its shape while the therapeutic agentis released into the surrounding anatomy for the desired duration ofrelease.

A length L of the elongated depot 100 can be about 2 mm to about 300 mm,about 10 mm to about 200 mm, or about 10 mm to about 100 mm. In someembodiments, the maximum cross-sectional dimension D of the depot 100can be between about 0.01 mm to about 5 mm, between about 0.1 mm toabout 3 mm, or between about 0.5 mm to about 2 mm. The elongated formmay be particularly well suited for injection or insertion to asubcutaneous, intramuscular, or other location through a needle or othersuitable delivery device. Additionally or alternatively, the elongateddepots 100 may be implanted using other techniques, for example surgicalimplantation through an open incision, a minimally invasive procedure(e.g. laparoscopic surgery), or any other suitable technique based onthe application.

FIG. 20 illustrates an example of an elongated, generally cylindricaldepot 100 comprising tubular, concentric therapeutic and control regions200 and 300. The therapeutic region 200 comprises a tubular sidewallhaving an outer surface covered by the control region 300 and an exposedinner surface defining a lumen 350 that extends through the length L ofthe depot 100. The lumen 350 can be devoid of any material such thatwhen the depot 100 is exposed to physiological fluid in vivo, the innersurface of the therapeutic region 200 is in direct contact with thefluid, thereby enhancing release of the therapeutic agent (relative toan elongated depot without a lumen through the therapeutic region). Asshown in FIG. 20, the end surfaces of the therapeutic region 200 at thelongitudinal ends 101, 103 of the depot 100 may also remainexposed/uncovered by the control region 300 (only one end surface isvisible in FIG. 20). In some embodiments, the elongated depot 100 mayinclude multiple, layered control regions 300 having the samecomposition or different compositions and/or the same thickness ordifferent thicknesses. In these and other embodiments, the controlregion 300 may extend over one or both end surfaces of the therapeuticregion 200. In particular embodiments, the lumen 350 extends throughonly a portion of the length L of the depot 100 and/or the tubulartherapeutic region 200 is not concentric with the control region 300.

In some embodiments, the elongated depot 100 may include multiple lumens(e.g., two, three, four, five, six, etc.) extending through all or aportion of the length of the depot 100 and/or the length of thetherapeutic region 200. For example, FIG. 21 is an end view of anelongated depot 100 having an inner therapeutic region 200 and an outercore region 300 covering an outer surface of the therapeutic region 200along its length. In this particular example, the depot 100 includesthree lumens 350 extending through the length of the therapeutic region200. In the illustrated embodiment, each of the lumens 350 has asubstantially circular cross-section and similar dimensions. In otherembodiments, the lumens 350 may have other cross-sectional shapes,and/or the dimensions of each lumen 350 may vary from one another. Insome embodiments, the elongated depot 100 may include multiple, layeredcontrol regions 300 having the same composition or differentcompositions and/or the same thickness or different thicknesses. Inthese and other embodiments, the control region 300 may extend over oneor both end surfaces of the therapeutic region 200.

As shown in the end view of FIG. 22, the depot 100 can include aplurality of separate therapeutic regions 200 (labeled 200 a-200 e)extending longitudinally along the length of the depot 100. Although thedepot 100 is shown having five therapeutic regions 200, in otherembodiments the depot 100 may have more or fewer therapeutic regions 200(e.g., two, three, four, six, seven, eight, etc.). The therapeuticregions 200 may be separated from one another by the control region 300.In the illustrated example, a central lumen 350 extends through thelength of the control region 300, and the therapeutic regions 200 aredistributed around the central lumen 350. In other embodiments, theelongated depot 100 may not include a lumen extending through any of itsregions and may be solid across its cross-sectional dimension.

The therapeutic regions 200 a-200 e may have the same or differentcompositions, shapes, and/or dimensions. For example, the therapeuticregions 200 a-200 e may contain the same or different therapeuticagents, the same or different amount of therapeutic agent, the same ordifferent polymers, and/or the same or different concentrations ofreleasing agents, depending on the desired release profile of each ofthe therapeutic regions 200 a-200 e. In the illustrated embodiment, eachof the elongated therapeutic regions 200 has a substantially circularcross-section and similar dimensions. In other embodiments, theelongated therapeutic regions 200 may have other cross-sectional shapesand/or dimensions. In some embodiments, the elongated depot 100 mayinclude one or more additional control regions 300 layered on top of theinner control region 300 surrounding the therapeutic regions 200 a-200e. having the same composition or different compositions and/or the samethickness or different thicknesses. In these and other embodiments, thecontrol region 300 may extend over one or both end surfaces of thetherapeutic region 200.

FIG. 23 illustrates another embodiment of an elongated depot 100 inwhich the cross-sectional area is composed of three elongatedtherapeutic regions 200 a-200 c separated radially from one another bythree elongated control regions 300. In the illustrated embodiment, eachof the separate regions intersects at a center in a pie-shapedconfiguration, however the constituent control regions 300 a-300 c andtherapeutic regions 200 a-200 c can take any shape and form in differentembodiments. Optionally, the depot 100 may include an additional controlregion 300 d covering an outer surface of the more inner therapeuticregions 300 a-300 c and control regions 300 a-300 c to provide anotherlayer of controlled release. In some embodiments, the elongated depot100 may include multiple, layered control regions 300 having the samecomposition or different compositions and/or the same thickness ordifferent thicknesses. In these and other embodiments, the controlregion 300 may extend over one or both end surfaces of the therapeuticregion 200.

In certain instances, it may be beneficial to provide an elongated depot100 having an inner therapeutic region 200 and an outer control region300 of variable thickness and/or non-uniform coverage. Several examplesof such depots 100 are shown FIGS. 24A-28. As depicted in FIGS. 24A-24C,the depot 100 can include an elongated therapeutic region 200 having asubstantially uniform cross-sectional profile. The outer control region300 radially surrounds the therapeutic region 200 along the length ofthe depot 100 and has a thickness that varies along the length of thedepot 100. As shown in FIG. 24A, the control region 300 may havealternating first and second portions 305, 307 along its length. Thefirst portions 302 can have a first thickness and the second portions304 can have a second thickness greater than the first thickness. Assuch, the first portions 302 form annular grooves within the controlregion 300 at the outer surface of the depot 100. When implanted, thethinner first portions 302 may release the therapeutic agent morequickly than the thicker second portions 304, as the therapeutic agenthas less control region to travel through before leaving the depot 100.By separately providing for faster-releasing portions andslower-releasing portions of the depot 100, the overall release rate oftherapeutic agent from the therapeutic region 200 to a treatment sitecan be precisely tailored to a desired application. In addition tocontrolling the overall release rate, the release of therapeuticagent(s) can be spatially controlled, for example by directing a firsttherapeutic agent towards a first portion of the treatment site and asecond therapeutic agent towards a second portion of the treatment site.

As shown in FIG. 24D, in some embodiments the elongated therapeuticregion 200 may have different therapeutic agents disposed at differentsections 200 a, 200 b along the length of the therapeutic region 200,where each section having a different therapeutic agent is axiallyaligned with a corresponding section of the control region 300 that hasa thickness that is specific to the desired release profile of theunderlying therapeutic agent. For example, in some applications it maybe beneficial to release a first therapeutic agent at a faster rate andshorter duration and a second therapeutic agent at a slower rate for alonger duration. In such instances, the elongated therapeutic region 200may have a first section 200 a containing the first therapeutic agent(and optionally a polymer and/or releasing agent) and a second section200 b adjacent the first section 200 a along the length of thetherapeutic region 200 that has a second therapeutic agent (andoptionally a polymer and/or releasing agent). The first section 302 ofthe control region 300 surrounding the first section 200 a may have athickness that is less than a thickness of the second section 304 of thecontrol region 300 surrounding the second section 200 b. As such, thefirst therapeutic agent contained in the first section 200 a may releaseat a faster rate than the second therapeutic agent contained in thesecond section 200 b. In some embodiments, a depot 100 can be configuredto deliver two, three, four, five, or more different therapeutic agents,any or all of which can have different rates and times of release fromthe depot 100.

FIG. 25 illustrates another embodiment of an elongated depot 100comprising an inner therapeutic region 200 radially surrounded by anouter control region 300. In the illustrated embodiment, the controlregion 300 includes three discrete sections 302, 304, 306 havingincreasing thickness. Although these increases in thickness are shown asstep-changes between discrete sections, in other embodiments there maybe a gradual taper or change in thickness of the control region 300 overthe length of the depot 100. In some embodiments, the number of discretesections may be varied as desired (e.g., two, four, five, six, seven,eight, nine, ten, or more discrete sections), and each discrete sectionmay have an increased or decreased thickness and/or length relative toadjacent discrete sections. Each discrete section may be positionedaround a corresponding section of the therapeutic region 200, and eachsection of the therapeutic region may include the same therapeuticagent, or may include different therapeutic agents as described withrespect to FIG. 24D.

FIGS. 26-28 depict examples of elongated depots 100 comprising an innertherapeutic region 200 radially surrounded by an outer control region300, where the outer control region 300 has one or more windows oropenings extending through the entire thickness of the control region300 to expose the underlying therapeutic region 200 through theopening(s). The openings can be notched into or laser cut from thecontrol region 300, or the therapeutic region 200 can be masked whilethe control region 300 is applied (e.g., via spray- or dip-coating) toachieve the desired openings. The opening(s) provide a more rapidrelease route for the therapeutic agent to operate in concert with themore gradual release of therapeutic agent through the covered portionsof the therapeutic region. The geometry of the opening(s) may be variedas desired, and can include squares, rectangles, circles, ellipses,slits, polygonal shapes, linear shapes, non-linear shapes, orcombinations thereof.

As shown in FIG. 26, in some embodiments the openings may comprise aplurality of windows 308, some or all of which may extend around all ora portion of the circumference of the depot 100 and may be spaced apartalong the length of the depot 100. FIG. 27 illustrates anotherembodiment of an elongated depot 100 in which the control region 300 isprovided with a single elongated slit or opening 310. The opening 310extends along the entire length of the control region 300 and/or depot100 such that the control region 300 has a C-shape in cross-section. Inthe illustrated embodiment, the opening 310 extends substantiallystraight along a path parallel to the long axis of the depot 100,however in other embodiments the opening 310 may be curved, windhelically around the depot 100, or take any other suitable shape. Thedepot 100 shown in FIG. 28 is similar to that of FIGS. 26 and 27 exceptthat the openings 350 are a plurality of circular holes or aperturesextending through the thickness of the control region 300.

FIGS. 29A and 29B are side and end cross-sectional views, respectively,of an elongated depot 100 comprising first and second elongatedtherapeutic regions 200 a and 200 b extending longitudinally within asurrounding control region 300. In the depicted embodiment, the centrallongitudinal axes of first and second therapeutic regions 200 a and 200b are offset from each other and from the central longitudinal axis ofthe control region 300. In some embodiments, the first therapeuticregion 200 a can be configured to release the therapeutic agent morequickly than the second therapeutic region 200 b, for example by varyingthe releasing agent concentration (if present), the therapeutic agentconcentration, the polymer composition (if present), or other propertiesof the respective therapeutic regions 200 a and 200 b. The first andsecond therapeutic regions 200 a and 200 b can contain the same ordifferent therapeutic agents.

The depot 100 shown in FIG. 30 is similar to that of FIG. 29A exceptthat each therapeutic region 200 a is interspersed along its length bybarrier regions 400. As noted previously, certain embodiments of thedepots 100 described herein employ barrier regions that present abarrier to physiologic fluids. In one embodiment, one or more of thebarrier regions 400 may comprise a bioresorbable polymer without anyreleasing agent. In another embodiment, one or more of the barrierregions 400 can include a delayed release agent mixed with abioresorbable polymer, but without a releasing agent.

As depicted in FIG. 30, the first therapeutic region 400 a isinterspersed with three barrier regions 400 of a first length, while thesecond therapeutic region 200 b is interspersed with four delayedrelease regions 400 having a shorter length. The relative lengths,number, composition, and spacing of the barrier regions 400 can beselected to achieve the desired release profiles. In operation, anexposed portion of the first or second therapeutic regions 200 a or 200b may release therapeutic agent relatively quickly. However, once thetherapeutic region 200 a or 200 b has been eroded and the exposed faceof the depot 100 is a barrier region 400, the release of therapeuticagent from that particular therapeutic region may drop significantly.Accordingly, the use of such barrier regions 400 can allow for highlycontrolled release, with multiple periods of relatively steady releaseof therapeutic agent punctuated by periods in which little or notherapeutic agent is released due to the presence of the barrier regions400.

FIG. 31 illustrates a depot 100 in which the inner therapeutic region200 is continuous along the length of the depot 100, while the controlregion 300 is punctuated by barrier regions 400. The incorporation ofthese barrier regions 400 reduces the exposed surface area of thecontrol region 300 and thereby decreases the rate of release oftherapeutic agent from the depot 100.

In the embodiments shown in FIG. 32-35, the elongated, columnar depot100 includes first and second end caps formed of barrier regions 400.This configuration can eliminate the exposed surface at the ends of thecolumnar structure, thereby reducing the rate of release of therapeuticagent from the therapeutic region 200. As seen in FIGS. 32 and 33, theend caps formed of barrier regions 400 can have a diameter orcross-sectional transverse dimension substantially similar to that ofthe control region 300, such that the outer surface of the controlregion 300 is coplanar with a radially outermost surface of the barrierregions 400 forming the end caps.

In the embodiment shown in FIG. 33, the depot 100 includes first andsecond therapeutic regions 200 a and 200 b that are coaxially alignedand directly adjacent to one another (e.g., arranged in an end-to-endfashion along their longitudinal axes), while in FIGS. 34 and 35 theadjacent therapeutic regions 200 a-200 c are separated from one anotherby intervening barrier regions 400. FIG. 34 additionally shows optionalend caps 400 that extend further radially, for example as shown inSection I, the end caps formed by barrier regions 400 can have the samediameter or transverse dimension as the control region 300, oralternatively as shown in section II, the barrier regions 400 formingthe end caps can project radially beyond the control region 300. In someembodiments, as best seen in FIG. 35, the thickness of the barrierregions 400 can vary across the depot 100 in order to achieve thedesired release profile.

FIGS. 36A-39B illustrate various configurations of a depot 100containing one or more therapeutic regions 200 that are at leastpartially surrounded by one or more control regions 300 and/or one ormore barrier regions 400, with a form factor configured to provide thedesired release profile. As noted previously, different therapeuticregions 200 can vary from one another in the composition of therapeuticagent(s) contained therein, the concentration of therapeutic agent(s)contained therein, polymer composition, or any other parameter that canvary the release profile. Similarly, in some embodiments the depot 100may include multiple, layered control regions 300 and/or barrier regions400 having the same composition or different compositions and/or thesame thickness or different thicknesses. These depots 100 that include aplurality of different therapeutic regions 200, a plurality of differentcontrol regions 300, and/or a plurality of different barrier regions 400can allow for controlled release of a single therapeutic agent ormultiple different therapeutic agents according to a desired releaseprofile. For example, in some applications it may be beneficial torelease a first therapeutic agent at a faster rate and shorter durationand a second therapeutic agent at a slower rate for a longer duration.As described in more detail below, by varying the configuration andcomposition of the depots 100, the release profile of therapeuticagent(s) can be sequential (in the case of multiple therapeutic agents),delayed, zero-order, or otherwise.

In some embodiments, a plurality of depots can be provided together (forexample as a kit, an assembly, pre-loaded into a delivery device such asa syringe, etc.). In some embodiments, the depots can have a variety ofdifferent release profiles. For example, a system can include aplurality of depots selected from at least two of the following groups:(1) depots configured to provide for a substantially immediate burstrelease of therapeutic agent, (2) depots configured to provide for asubstantially first-order release of therapeutic agent, (3) depotsconfigured to provide for a substantially zero-order release oftherapeutic agent, and (4) depots configured to exhibit delayed releaseof therapeutic agents (as discussed below with respect to FIGS.39A-39B).

FIG. 36A shows a side view of a depot 100, and FIG. 36B shows across-sectional view taken along line B-B in FIG. 36A. As seen in FIGS.36A-36B, in some embodiments the first therapeutic region 200 a canenvelop or at least partially or completely surround the secondtherapeutic region 200 b. As a result, the first therapeutic region 200a will release its therapeutic agent(s) first, and release oftherapeutic agent(s) from the second therapeutic region 200 b will berelatively delayed. In some embodiments, the first therapeutic region200 a completely encapsulates the second therapeutic region 200 b, suchthat no surfaces of the second therapeutic region 200 b are directlyexposed to physiologic fluids upon implantation in a patient's body. Inother embodiments, the second therapeutic region 200 b can be exposedalong at least one face, thereby allowing more immediate release oftherapeutic agent from the second therapeutic region 200 b. In theillustrated embodiment, the first and second therapeutic regions 200 aand 200 b are arranged concentrically around the long axis of the depot100, however in other embodiments the second therapeutic region 200 bmay be off-center, such that the first therapeutic region 200 a isthicker along one side of the second therapeutic region 200 b than alonganother side.

In the embodiment shown in FIG. 36C, first and second therapeuticregions 200 a and 200 b are arranged in an end-to-end fashion (e.g., indirect contact with one another), while a parallel third therapeuticregion 200 c extends along the length of the depot 100 and contacts boththe first and second therapeutic regions 200 a and 200 b. FIG. 36Dillustrates another embodiment in which first and second therapeuticregions 200 a and 200 b are arranged end-to-end and aligned along thelength of the depot 100. These embodiments may be used to achievedirectional release of therapeutic agents, e.g., the therapeutic agentof the first therapeutic region 200 a is primarily released from a firstend of the depot 100, and the therapeutic agent of the secondtherapeutic region 200 b is primarily released from a second, oppositeend of the depot 100, while the therapeutic agent of the thirdtherapeutic region 200 c releases from both ends of the depot 100.

FIG. 37A illustrates a depot 100 configured to release therapeuticagent(s) from first and second therapeutic regions 200 a and 200 b in asequential manner. As seen in FIG. 37A, the first therapeutic region 200a is partially covered by an overlying control region 300. The firsttherapeutic region 200 a in turn overlies a first barrier region 400 a.In the illustrated embodiment, the first therapeutic region 200 a, thecontrol region 300, and the first barrier region 400 a each extend theentire length of the depot 100 and are each exposed along the sidesurfaces of the depot 100, however in other embodiments side surfacesmay be covered completely or partially by a control region 300 and/or abarrier region 400. Beneath the first barrier region 400 a is the secondtherapeutic region 200 b, which may contain the same or differentpolymer composition and/or therapeutic agent as the first therapeuticregion 200 a. The second therapeutic region 200 b is surroundedlaterally by a second barrier region 400 b, which also extends beneaththe second therapeutic region 200 b. As a result, the second therapeuticregion 200 b has at least one surface in contact with the first barrierregion 400 a and one or more remaining surfaces in contact with thesecond barrier region 400 b, such that the second therapeutic region 200b is completely encapsulated by the first and second barrier regions 400a, 400 b. In some embodiments, one or both of the barrier regions 400 aand 400 b can be substituted for control regions having a lowerconcentration of release agent than the control region 300.

As noted previously, barrier regions may present a barrier tophysiologic fluids, for example by comprising a bioresorbable polymerwithout any releasing agent, or a delayed release agent mixed with abioresorbable polymer, but without a releasing agent. The first barrierregion 400 a and the second barrier region 400 b may differ from oneanother in composition, thickness, or any other parameters affectingdissolution of the barrier regions 400 a and 400 b. In some embodiments,the second barrier region 400 b can be configured to dissolve moreslowly than the first barrier region 400 a, such that, after the firstbarrier region 400 a has partially or completely dissolved, the secondbarrier region 400 b remains intact and continues to block or delaypassage of physiologic fluids therethrough.

In operation, the first barrier region 400 a dissolves more slowly thaneither the control region 300 or the first and second therapeuticregions 200 a and 200 b, and therefore presents a barrier tophysiological fluids passing through the first barrier region 400 a. Asa result, when the depot 100 is first placed into contact withphysiologic fluids, the release agent of the control region 300 maybegin to dissolve, thereby creating diffusion openings for thetherapeutic agent(s) in the first therapeutic region 200 a to escapetherethrough. The therapeutic agent(s) in the first therapeutic region200 a may also escape directly through the exposed surfaces of the firsttherapeutic region 200 a. However, at least in the initial periodfollowing implantation, the first barrier region 400 a may stop or slowthe passage of physiologic fluids through the barrier region 400 a andto the underlying second therapeutic region 200 b, such that thetherapeutic agent(s) within the second therapeutic region 200 b exhibitsminimal or no release in the initial period. After a first period oftime, the control region 300, first therapeutic region 200 a and/or thefirst barrier region 400 a may be partially or completely dissolved,thereby allowing at least some physiologic fluid to pass therethroughand come into contact with the second therapeutic region 200 b. At thispoint, therapeutic agent(s) contained within the second therapeuticregion 200 b may begin to be released from the depot 100, for example bypassing through openings formed in the first or second barrier regions400 a and 400 b. Accordingly, the depot 100 can be configured such thatall or substantially all (e.g., more than 80%, more than 90%) of thetherapeutic agent(s) from the first therapeutic region 200 a arereleased from the depot 100 before the therapeutic agent(s) from thesecond therapeutic region 200 b are released in any substantial quantity(e.g., more than 1%, more than 5%, more than 10% of the therapeuticagent(s) contained within the second therapeutic region 200 b). In someembodiments, the therapeutic agent(s) from the second therapeutic region200 b are not released in any substantial quantity until at least 12hours, at least 18 hours, at least 24 hours, at least 36 hours, at least48 hours, at least 3 days, at least 4 days, at least 5 days, at least 6days, at least 7 days, at least 8 days, at least 9 days, at least 10days, at least 11 days, at least 12 days, at least 13 days, at least 2weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10weeks, at least 11 weeks, or at least 12 weeks after implantation of thedepot 100 and/or after release of substantially all of the therapeuticagent(s) from the first therapeutic region 200 a.

In one example, the control region 300 is a PLGA film with a releasingagent, the first therapeutic region 200 a is a PLGA film loaded with afirst therapeutic agent (e.g., bupivacaine), the first barrier region400 a is a PLGA film with no releasing agent, the second therapeuticregion 200 b is a PLCL film loaded with a second therapeutic agent(e.g., 5-fluorouracil), and the second barrier region 400 b is a PLCLfilm with no releasing agent. As will be understood, the particularpolymers, therapeutic agents, releasing agents, concentrations thereof,and dimensions can be selected to achieve the desired release profilesof the first and second therapeutic agents and to achieve the desiredtotal erosion of the depot 100 after a predetermined period of time.

Examples of the release profile from the depot 100 of FIG. 37A areillustrated in FIG. 37B. In this example, Samples 1 and 2 were eachprepared with a configuration as shown in FIG. 37A with a thickness ofapproximately 1.8 mm and a length and width of approximately 20 mm. Thecontrol region 300 includes PLGA with polysorbate 20, commercially knownas Tween 20™ as a releasing agent, with the ratio of Tween to polymer of5:10. The first therapeutic region 200 a includes a PLGA polymer withTween 20 and bupivacaine HCl, with the ratio of tween to polymer tobupivacaine of 1:10:20. The first barrier region 400 a includes a PLGAfilm with no releasing agent or therapeutic agent, and the secondbarrier region 400 b includes a PLCL film with no releasing agent ortherapeutic agent. The second therapeutic region 200 b includes a PLCLpolymer with 5-FU and no releasing agent, with a polymer to 5-FU ratioof 1:1.

Referring to FIG. 37B, the “Drug 1” lines illustrate release of a firsttherapeutic agent from the first therapeutic region 200 a. The “Drug 2”lines illustrate release of a second therapeutic agent from the secondtherapeutic region 200 b, which is not released in any substantialamount until a first period has passed (approximately 19 days in theembodiment of FIG. 37B), after which the second therapeutic agent beginsto release from the depot 100. The result is a sequential release inwhich the first therapeutic agent is substantially completely released(e.g., more than 80%, more than 90%, more than 95%, more than 99% of thefirst therapeutic agent is released from the depot 100) before thesecond therapeutic agent begins to be released in any significant amount(e.g., more than 1%, more than 5%, or more than 10% of the secondtherapeutic agent is released from the depot 100).

FIG. 38A illustrates a depot 100 configured to release a therapeuticagent from a therapeutic region 200 in accordance with a substantiallyzero-order release profile. In the illustrated embodiment, the depot 100includes a therapeutic region 200 that is laterally surrounded by one ormore barrier regions 400. In some embodiments, the therapeutic region200 and the barrier region 400 can have a substantially similarthickness such that upper and lower surfaces of the therapeutic regionand the barrier region 400 are substantially coplanar. First and secondcontrol regions 300 can be disposed over upper and lower surfaces ofboth the therapeutic region 200 and the barrier region 400, such thatthe therapeutic region 200 is completely encapsulated by the first andsecond control regions 300 and the barrier region 400.

When the depot 100 is placed in contact with physiological fluids (e.g.,when implanted at a treatment site in vivo), the release agent in thecontrol regions 300 will begin to dissolve to form diffusion openingstherein, after which therapeutic agent(s) contained within thetherapeutic region 200 may begin to pass through to be released from thedepot 100. By virtue of the laterally disposed barrier regions 400,little or no therapeutic agent may pass from the therapeutic region 200through the barrier regions 400 for at least a period of time (e.g., atleast 1 day, at least 2 days, at least 3 days, at least 4 days, at least5 days, at least 6 days, at least 7 days, at least 8 days, at least 9days, at least 10 days, at least 11 days, at least 12 days, at least 13days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9weeks, at least 10 weeks, at least 11 weeks, or at least 12 weeks). As aresult, substantially linear release of therapeutic agent can beachieved by controlling the dimensions and composition of the controlregions 300 and the therapeutic region 200. As used herein,“substantially linear” includes a release profile in which the rate ofrelease over the specified time period does not vary by more than 5%, ormore than 10% from the average release rate over the time period. Thesubstantially linear release profile can be maintained over a desiredperiod of time, e.g., over at least 1 day, at least 2 days, at least 3days, at least 4 days, at least 5 days, at least 6 days, at least 7days, at least 8 days, at least 9 days, at least 10 days, at least 11days, at least 12 days, at least 13 days, at least 2 weeks, at least 3weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least11 weeks, or at least 12 weeks.

In one example, the control region 300 can be a PLCL or PLGA filmcontaining a releasing agent, the therapeutic region can be a PLCL filmloaded with a therapeutic agent (e.g., bupivacaine; 5-fluorouracil,etc.), and the barrier region 400 can be a PLCL film with no releasingagent. As will be understood, the particular polymers, therapeuticagents, releasing agents, concentrations thereof, and dimensions can beselected to achieve the desired release profiles of the therapeuticagent(s) and to achieve the desired total erosion of the depot 100 aftera predetermined period of time (e.g., approximately 40 days).

Examples of the release profile from the depot 100 of FIG. 38A areillustrated in FIG. 38B, with four samples with varying polymerconfigurations illustrated. In this example, Samples 1-4 were eachprepared with a configuration as shown in FIG. 38A with a thickness ofapproximately 0.8 mm and a length and width of approximately 20 mm.Samples 1 and 2 were prepared using the same configuration, in which thecontrol region 300 includes a PLCL polymer and Tween as a releasingagent with a Tween to polymer ratio of 1:2. The therapeutic region 200includes a PLCL polymer with 5-FU and no releasing agent, with a polymerto 5-FU ratio of 1:1, and the barrier region 400 includes a PLCL polymerwith no releasing agent. Samples 3 and 4 were prepared using the sameconfiguration, in which the control region 300 includes a PLGA polymerand Tween as a releasing agent with a Tween to polymer ratio of 1:2. Thetherapeutic region 200 includes a PLCL polymer with 5-FU and noreleasing agent, with a polymer to 5-FU ratio of 1:1, and the barrierregion 400 includes a PLGA polymer with no releasing agent.

As seen in FIG. 38B, by varying the polymer configurations (e.g.,composition, release agent, thickness, etc.), the zero-order releaseprofile can be tuned to release at different rates. In some embodiments,there is an initially higher rate of release for a first short period(e.g., approximately 1 day in the illustrated examples), followed by asubstantially linear release for the remaining period of time.

FIG. 39A illustrates a depot 100 configured to release a therapeuticagent from a therapeutic region 200 in accordance with a delayed releaseprofile, in which little or none of the therapeutic agent(s) arereleased in a first period (e.g., less than 10%, less than 20% of thetherapeutic agent(s) are released), followed by a rapid increase inrelease rate during a second period in which the therapeutic agent isreleased from the depot 100. In the illustrated embodiment, the depot100 includes a therapeutic region 200 that is at least partiallysurrounded on opposing sides (e.g., over top and bottom surfaces) bybarrier regions 400. In some embodiments, the therapeutic region 200 andthe barrier region 400 can have a substantially similar length and widthsuch that the therapeutic region 200 is exposed at one or more sidesurfaces of the depot 100.

When the depot 100 is placed in contact with physiological fluids (e.g.,when implanted at a treatment site in vivo), the therapeutic agent(s)contained within the therapeutic region 200 will pass from thetherapeutic region 200 into the surrounding environment through theexposed side surface(s) of the therapeutic region 200. In someembodiments, little or none of the therapeutic agent passes through thebarrier regions 400 during an initial period. During this period, arelatively small portion of the therapeutic agent may be releasedthrough the exposed side surfaces (e.g., less than 20%, less than 15%,less than 10%, or less than 5% of the therapeutic agent may bereleased). After the first time period, the barrier regions 400 maybegin to degrade, after which the therapeutic agent begins to bereleased through openings formed in the barrier regions 400. As aresult, the depot 100 achieves a delayed release in which little or noneof the therapeutic agent is released over a first time period (e.g.,more than 1 week, more than 2 weeks, more than 3 weeks, more than 4weeks, more than 5 weeks, more than 6 weeks, more than 7 weeks, morethan 8 weeks, more than 9 weeks, more than 10 weeks), after which thetherapeutic agent is released from the depot 100 at an increased rate.In some embodiments, the exposed side surfaces of the therapeutic region200 can be partially or completely covered by one or more controlregions 300 and/or by one or more barrier regions 400, which can furtherdelay release of the therapeutic agent from the therapeutic region 200.

In one example, the therapeutic region 200 can be a PLCL film loadedwith a therapeutic agent (e.g., bupivacaine; 5-fluorouracil, etc.), andthe barrier regions 400 can be PLGA film with no release agent or PLCLfilm with no release agent. As will be understood, the particularpolymers, therapeutic agents, concentrations thereof, and dimensions canbe selected to achieve the desired release profiles of the therapeuticagent and to achieve the desired total erosion of the depot 100 after apredetermined period of time.

Examples of the release profile from the depot 100 of FIG. 39A areillustrated in FIG. 39B. Samples 1 and 2 illustrate a release profilefor a bare therapeutic region with no surrounding barrier regions. Insamples 1 and 2, release of the therapeutic agent commences immediatelyafter exposure to fluid. Samples 3-6 were each prepared with aconfiguration as shown in FIG. 39A. Samples 3 and 4 were prepared usingthe same configuration, in which the control region 300 includes a PLCLpolymer and Tween as a releasing agent with a Tween to polymer ratio of1:2. The therapeutic region 200 includes a PLCL polymer with 5-FU and noreleasing agent, with a polymer to 5-FU ratio of 1:1, and the barrierregion 400 includes a PLCL polymer with no releasing agent.

Samples 3-6 illustrate different examples of release profiles for thedepot 100 of FIG. 39B with varying polymer configurations illustrated.In samples 3 and 4, the barrier regions 400 are made of a PLGA polymer,while in samples 5 and 6, the barrier regions 400 are made of a PLCLpolymer. In samples 3 and 4, release of the therapeutic agent is delayedfor approximately 2 weeks (e.g., less than 20%, less than 15%, less than10%, or less than 5% of the therapeutic agent is released from the depot100), after which the therapeutic agent is released from the depot 100at an increased rate (e.g., at least 2 times, at least 3 times, at least4 times, at least 5 times, or at least 10 times of the initial releaserate). In samples 5 and 6, release of the therapeutic agent delayed forapproximately 15 weeks (e.g., less than 20%, less than 15%, less than10%, or less than 5% of the therapeutic agent is released from the depot100), after which the therapeutic agent is released at an increased rate(e.g., at least 2 times, at least 3 times, at least 4 times, at least 5times, or at least 10 times of the initial release rate). The barrierregions 400 in samples 3 and 4 are configured to degrade more quicklythan the barrier regions 400 in samples 5 and 6, because PLGA degradesmore quickly than PLCL. As a result, the delay period in samples 3 and 4is shorter than the delay period in samples 5 and 6. In variousembodiments, the degradation rate of the barrier regions 400 can betuned by varying dimensions, selecting different polymers, or making anyother suitable modifications to the barrier regions 400. By varying thepolymer configurations (e.g., composition, thickness, etc.), the delayedrelease profile can be tuned to have different delay periods (e.g., aninitial period during which little or none of the therapeutic agent isreleased) and to release the therapeutic agent at different ratesfollowing the delay period.

In some embodiments, it can be beneficial to provide a plurality ofpre-formed openings or apertures extending through the depot 100, eitherin a regular or irregular pattern. Such openings can provide additionalpathways for a therapeutic agent to pass from the therapeutic region tothe treatment site, and as such can be controlled to vary the desiredrelease profile. For example, in some embodiments the openings orapertures permit at least some of the therapeutic agent to be releaseddirectly from the therapeutic region 200 to the surrounding area,without passing through any overlying control region 300. Thesepre-formed openings or apertures may differ from diffusion openingsformed by dissolution of releasing agent in that the openings orapertures are formed in the depot 100 prior to implantation in thepatient's body. The openings or apertures may be used in combinationwith diffusion openings formed by dissolution of releasing agent tomodulate the release profile of therapeutic agent. For example, a depot100 having openings or apertures may release therapeutic agent at ahigher rate than a depot 100 without openings or apertures.

FIG. 40A illustrates a depot 100 with a sponge-like configuration inwhich a plurality of irregular openings 350 are formed through the depot100. In some embodiments, such a depot 100 may be formed by introducingair or otherwise agitating the polymer composition during formation ofthe depot 100 and while encouraging the solvent to evaporate, resultingin a porous depot 100 with a plurality of openings therein. Such a depot100 can be substantially uniform in its composition or can include anouter control region and an inner therapeutic region, one or both ofwhich are permeated by some or all of the openings formed in the depot100.

FIG. 40B illustrates a depot 100 in which a plurality of openings 350extend through a thickness of the depot 100. In the illustratedembodiment, the openings 350 are substantially cylindrical and passthrough upper and lower control regions 300 as well as an innertherapeutic region 200 along substantially parallel trajectories. Inother embodiments, the openings 350 can assume other cross-sectionalshapes, extend along other axes, and/or vary among one another inorientation, size, shape, etc.

In some instances, it can be useful to provide a depot that has acurved, bent, or rounded configuration. For example, such curved depotscan beneficially provide adequate contact with a curved surface area ofa treatment site, such as the interior of a bladder, an abdominal wall,a surface of a tumor, or any other suitable treatment site. In someembodiments, the depot can have a substantially straight configurationprior to being deployed in vivo and the curved configuration can beachieved after the depot 100 is deployed in vivo in the presence ofphysiological fluids, while in other embodiments the depot 100 can havemaintain the curved configuration both prior to and after being deployedin vivo. FIGS. 41A-44 illustrate various examples of depots 100 havingcurved configurations. With reference to FIGS. 41A-B, the depot 100 canhave an actuating region 320 that is less elastic than a therapeuticregion 200. For example, the actuating region 320 can have a differentcomposition, different dimensions, and/or can be manufactured accordingto different processes than the therapeutic region 200. By stretchingthe depot 100 beyond the elastic hysteresis point of the less elasticactuating region 320, the depot 100 can transition from thesubstantially straightened configuration (shown in FIG. 41A) to thecurved configuration (shown in FIG. 41B), in which the less elasticactuating region 320 pulls the depot 100 into the curved shape. In someembodiments, this stretching can occur after implantation, while inother instances the stretching is performed during manufacturing or by asurgeon before implantation. In some embodiments, this transitioninvolves plastic deformation of the depot 100, such that the depot 100maintains the curved shape even after the stretching force has beenremoved.

A similar result can be achieved by varying the polymer compositions ofdifferent layers or regions as in FIGS. 42A-42B. For example a firstregion 322 may have a polymer composition that is more hydrophilic thana second region 324, and accordingly the first region 322 may absorbmore water or other fluids when implanted in vivo than the second region324. In various embodiments, either or both of the first and secondregions 322, 324 can carry a therapeutic agent. In the embodimentillustrated in FIGS. 42A-42B, the second region 324 is made ofpoly(L-lactic acid) (PLLA) and the first region 322 is made ofpolycaprolactone (PCL). In the presence of water, the PCL willexperience a higher water uptake than the PLLA when placed in thepresence of fluids. As a result, the PCL expands to a greater degreethan the PLLA, resulting in a transition from the straightened state(shown in FIG. 42A) to the curved state (shown in FIG. 42B). In thisembodiment, the depot 100 may advantageously retain the straightenedstate until it is deployed in vivo at the treatment site, at which pointthe depot 100 will begin to absorb water, resulting in a transition tothe curved state.

FIGS. 43A-43C illustrate another mechanism for achieving a curved depot.As shown in FIGS. 43A and 43B, the depot 100 may include an outer regionB and an axially offset inner region A. The inner region A can have adifferent composition (e.g., different polymer, the presence oftherapeutic agent, etc.) compared to the outer region B. Because theinner region A if offset from the axial centerline of the depot 100, adifference in elasticity or expansion between the inner region A and theouter region B can result in curvature of the depot 100. In one example,the inner region A may include PLLA and the outer region B may includePCL, such that when exposed to water, outer region B expands more thanthe inner region A, resulting in a curved state.

As noted previously, a curved depot 100 may advantageously be deployedagainst a curved treatment site, for example in apposition with aconcavely curved tissue surface (e.g., the interior of the bladder) asshown in FIG. 44, or in apposition with a convexly curved tissue surface(e.g., over a surface of a protruding tumor) as shown in FIG. 45. Inother embodiments, the depot 100 may be configured to have a morecomplex curvature, for example at least one concave region and at leastone convex region, or having different regions with different degrees ofcurvature. Such complex curvature can be tailored to achieve tissueapposition at a desired treatment site, and can improve delivery oftherapeutic agent to the treatment site.

As shown in FIGS. 46 and 47, in some embodiments a treatment device caninclude an anchoring member 500 and a depot 100 carried on a surface ofthe anchoring member 500. The anchoring member 500 may be a generallyhemispherical (as in FIG. 46), spherical (as in FIG. 47), or othersuitable structure configured to expand from a low-profile state to adeployed state in apposition with a treatment site. The anchoring member500 is configured to provide structural support to the treatment device,engage the adjacent anatomy (e.g., a bladder, etc.) to secure thetreatment device to a selected treatment site.

In some embodiments, the depot 100 is bonded or otherwise adhered to thesurface of the anchoring member 500. In other embodiments, the treatmentdevice may include a depot 100 without an anchoring member 500. Thedepot 100 may comprise a biocompatible carrier loaded with one or moretherapeutic agents and configured for a controlled, sustained release ofthe therapeutic agent(s) following in vivo placement of the depot. Insome embodiments, the depot may be a thin, multilayer film loaded with atherapeutic agent, wherein, as described herein, the depot 100 isconfigured to release the therapeutic agent(s) at the treatment site.

In some embodiments the structure forming the anchoring member 500 maybe a mesh structure. As used herein, “mesh” or “mesh structure” refersto any material (or combination of materials) having one or moreopenings extending therethrough. For example, in some embodiments, theanchoring member 500 comprises a plurality of filaments (e.g., wires,threads, sutures, fibers, etc.) that have been braided or woven into atubular shape and heat set. In some embodiments, the mesh structure maybe a stent formed of a laser-cut tube or laser-cut sheet, or the meshstructure may be a stent formed via thin film deposition. The anchoringmember 500 may be in the form of a flat wire coil attached to a singlelongitudinal strut, a slotted tube, a helical band that extendscircumferentially and longitudinally along the length of the anchoringmember, a modular ring, a coil, a basket, a plurality of rings attachedby one or more longitudinal struts, a braided tube surrounding a stent,a stent surrounding a braided tube, and/or any suitable configuration orembodiment disclosed herein.

In some embodiments, the anchoring member 500 may be formed of asuperelastic material (e.g., nickel-titanium alloys, etc.) or otherresilient materials such as stainless steel, cobalt-chromium alloys,etc. configured to self-expand when released from a delivery catheter.For example, the anchoring member may self-expand when pushed throughthe distal opening of the catheter, or by the delivery catheter beingpulled proximally of the anchoring member. In some embodiments theanchoring member 500 may self-expand upon release from otherconstraining mechanisms (e.g., removable filaments, etc.). In someembodiments, the anchoring member 500 may be expanded manually (e.g.,via balloon expansion, a push wire, a pull wire, etc.).

In some embodiments, the anchoring member 500 includes gold, magnesium,iridium, chromium, stainless steel, zinc, titanium, tantalum, and/oralloys of any of the foregoing metals or including any combination ofthe foregoing metals. In some embodiments, the anchoring member 500 mayinclude collagen or other suitable bioresorbable materials such as PLA,PLG, PLGA etc. In certain embodiments, the metal comprising the meshstructure may be highly polished and/or surface treated to furtherimprove its hemocompatibility. The anchoring member 500 may beconstructed solely from metallic materials without the inclusion of anypolymer materials, or may include a combination of polymer and metallicmaterials. For example, in some embodiments the anchoring member 500 mayinclude silicone, polyurethane, polyethylene, polyesters,polyorthoesters, polyanhyrides, and other suitable polymers. Thispolymer may form a complete sphere or hemisphere to block passage oftumor or drug though the anchoring member 500, or it may havemicroscopic pores to allow passage of drug but not tumor cells, or itmay have small or large openings. In addition, all or a portion of theanchoring member may include a radiopaque coating to improvevisualization of the device during delivery, and/or the anchoring member500 may include one or more radiopaque markers.

In some embodiments, the anchoring member 500 may have other suitableshapes, sizes, and configurations. To improve fixation, in someembodiments the anchoring member 500 may have one or more protrusionsextending radially outwardly from the mesh structure along all or aportion of its length, the one or more protrusions being configured toengage with tissue at the treatment site. For example, the anchoringmember 500 may include one or more barbs, hooks, ribs, tines, and/orother suitable traumatic or atraumatic fixation members.

As previously mentioned, the depot 100 may be bonded or otherwiseadhered to an outer surface of the anchoring member 500. For example,the depot 100 may be bonded to the anchoring member 500 by adhesivebonding, such as cyanoacrylate or UV curing medical grade adhesive,chemical or solvent bonding, and/or thermal bonding, and other suitablemeans. The depot 100 may also be sewn or riveted to the anchoring member500. In some embodiments, the depot 100 may be woven into the anchoringmember 500 at one or more sections of the anchoring member 500. In someembodiments, the anchoring member 500 may be dip coated in a solutioncomprising the material elements of the depot 100, and/or the anchoringmember 500 may be spray coated with the depot 100. Sections of theanchoring member 500 may be selectively masked such that only certainportions of the anchoring member 500 may be coated with the depot 100.In some embodiments, the anchoring member 500 may be originally in theform of a sheet, and the sheet may be embedded into the depot 100 (forexample, with the depot 100 as a multilayer film construction.) Theresulting sheet structure (i.e., the anchoring member 500 embeddedwithin the depot 100) may be rolled into a tubular structure (with orwithout the adjacent ends attached) for delivery into the body. In someembodiments, the depot may be coated with a bioresorbable adhesivederived from polyethylene glycol (PEG or PEO), for example, or fromother hydrogels. The PEG or hydrogel may also be integral to the depot100 via mixing in solution with the depot materials and not a separatecoating.

The depot 100 may be disposed along all or a portion of the surface ofthe anchoring member 500, all or a portion of the circumference of themesh structure, and/or cover or span all or some of the openings in themesh structure depending on the local anatomy of the treatment site. Forexample, the volume, shape, and coverage of the tumor may varypatient-to-patient. In some cases, it may be desirable to use atreatment device having a depot 100 extending around the entire outersurface and/or inner surface of the anchoring member 500. In othercases, it may be desirable to use a treatment device having a depot 100extending around less than the entire outer surface and/or inner surfaceof the anchoring member 500 to reduce exposure of potentially healthytissue to the chemotherapeutic agents.

In some cases, the depot 100 may be elastically expandable, such thatthe depot 100 expands with the anchoring member 500 as it is deployed.The depot 100 may also be less elastic but can be folded for delivery ina compact form. Alternatively, the depot 100 could be configured tochange shape as it is expanded. For example, a tubular depot could havea pattern of overlapping longitudinal slots, so that it expands into adiamond-shaped pattern as it is expanded. The expanded pattern of thedepot 100 may align with the pattern of the anchoring member 500, or itmay be totally independent of the anchoring member 500. This approachmay enable the highest volume of therapeutic agent to be delivered inthe most compact delivery format, while still enabling expansion ondelivery and flexion, compression and expansion while positioned at thetreatment site.

In certain cases, it can be useful to provide a depot 100 with a largeropening or lumen 350 therethrough. For example, a depot 100 deployed ina bladder may benefit from a relatively large opening that allows urineto pass therethrough. Such an opening can reduce the risk of the depot100 interfering with normal physiological function. FIGS. 48A and 48Billustrate two different embodiments of such depots 100. As seen in FIG.48A, the depot 100 can be substantially annular or ring-like structurewith a central opening 350. For example, the central opening 350 canhave a greatest transverse dimension that is more than 10%, more than20%, more than 30%, more than 40%, or more than 50% of the length of amaximum transverse dimension and the annular depot 100. In theembodiment shown in FIG. 48B, the depot 100 can be a curved (e.g.,semi-spherical or semi-ellipsoid) structure with a central opening 350configured to allow fluid to pass therethrough. Although single openings350 are illustrated in these embodiments, in other embodiments there maybe two or more openings 350 configured to facilitate normalphysiological function when the depot 100 is implanted at a treatmentsite.

FIGS. 49A-C illustrate perspective, top, and cross-sectional views,respectively, of a depot 100 having an annular semi-annular shape. Asillustrated, the depot 100 is an elongated strip, ribbon, or band thatcurls about an axis A. The depot 100 in the form of an elongated striphas an inwardly facing lateral surface 144 a and an outwardly facinglateral surface 144 b each having a width W. First and side secondsurfaces 144 c and 144 d can extend between the lateral surfaces 144 aand 144 b, defining a thickness T, such that the depot has asubstantially rectangular cross-section as seen in FIG. 49C. In someembodiments, the band can have a thickness T of between about 0.1 mm andabout 10 mm, or between about 0.5 mm and about 5 mm, or about 2 mm. Insome embodiments, the depot 100 can have a height H of between about 0.1mm and about 10 mm, or between about 0.5 mm and about 5 mm, or about 1mm. The depot 100 can be curled about the axis A such that first andseconds ends are adjacent to one another, while leaving a gap 145therebetween. In this curled configuration, the depot 100 ischaracterized by an inner diameter D. In some embodiments, for examplefor use in a bladder, the diameter D can be between about 2 cm and about20 cm, for example between about 2 cm and about 10 cm, or between about4 cm and about 8 cm, or approximately 6 cm. In some embodiments, thedepot 100 can have a length of between about 20 cm and about 100 cm, forexample between about 30 cm and about 50 cm, or approximately 38 cm.

In some embodiments, the ends can be joined together, creating a closedannular shape. As seen in FIG. 49C, in some embodiments the depot 100includes a control region 300 disposed on the inwardly facing lateralsurface 144 a and another control region 300 b disposed on the outwardlyfacing lateral surface 144 b. In some embodiments, a therapeutic region200 disposed between the two control regions 200 can be partially orcompletely exposed along the side surface 144 c. Optionally, thetherapeutic region 200 can also be partially or completely exposed alongan opposing side surface 144 d disposed opposite the first side surface144 c.

In some embodiments, the depot 100 of FIGS. 49A-49C can be delivered tothe treatment site in a compressed configuration, either straightenedlongitudinally, or curled tightly about a central axis, or othercompressed state. When delivered, the depot 100 can expand into theannular or semi-annular configuration as shown in FIG. 49A. In someembodiments, the depot 100 can be positioned such that the outwardlyfacing lateral surface 144 b is in apposition with tissue along at leasta portion of its length.

FIG. 50A shows an end view of a depot 100 in a spirally curled state andFIG. 50B shows a side view of the depot 100 in an uncurled state. Thedepot 100 includes a plurality of segments I-IV having differentstructural and mechanical properties that cause the depot 100 to assumethe spirally curled configuration shown in FIG. 50A when placed in thepresence of physiological fluids in vivo at a treatment site. Forexample, the different segments I-IV can vary in polymer composition,therapeutic agent, concentration of therapeutic agent, concentration ofrelease agent, or any other parameter that affects the mechanical andstructural properties of the depot 100, resulting in a spirally wounddepot 100 as seen in FIG. 50A. In some embodiments, the spiral windingcan facilitate placement of the depot 100 at a treatment site, and/orimprove attachment to anatomical tissue at the treatment site.

FIG. 51 illustrates a plurality of depots 100 in the form of microbeads,microspheres or particles. In various embodiments, each microbead caninclude a therapeutic region at its core and one or more control regionspartially, substantially, or completely surrounding the therapeuticregion. In some embodiments, the microbead may include multiple, layeredcontrol regions and/or therapeutic regions having the same compositionor different compositions and/or the same thickness or differentthicknesses. The release profile of any particular microbead isdetermined by its size, composition, and the thickness of the controlregion and therapeutic region. In some embodiments, a plurality ofmicrobeads are provided having varying dimensions, varying shapes (e.g.spherical, ellipsoid, etc.), varying polymer compositions, varyingconcentration of therapeutic agent in the therapeutic region, varyingconcentration of releasing agent in the control region, or variation ofany other parameters that affect the release profile. As a result, thecomposite release profile of the plurality of microbeads can be finelytuned to achieve the desired cumulative release of therapeutic agent tothe treatment site. In various embodiments, some or all of themicrobeads can have a diameter or largest cross-sectional dimension ofbetween about 0.01 to about 5 mm, or between about 0.1 mm to about 1.0mm. In some embodiments, some or all of the microbeads can have adiameter or largest cross-sectional dimension that is less than about 5mm, less than about 2 mm, less than about 1.0 mm, less than about 0.9mm, less than about 0.8 mm, less than about 0.7 mm, less than about 0.6mm, less than about 0.5 mm, less than about 0.4 mm, less than about 0.3mm, less than about 0.2 mm, or less than about 0.1 mm.

FIGS. 52A and 52B illustrate end and side views, respectively, of aplurality of depots 100 in the form of pellets. In the illustratedembodiment, the pellets are substantially cylindrical, however theparticular shape and dimensions of the pellets may vary to achieve thedesired release kinetics and form factor. For example, the pellets canhave rounded ends (e.g., ellipsoid), and/or can have a cross-sectionalshape that is circular, elliptical, square, rectangular, regularpolygonal, irregular polygonal, or any other suitable shape. In someembodiments, each pellet can include an inner therapeutic region atleast partially surrounded by an outer control region. In someembodiments, the pellet may include multiple, layered control regionsand/or therapeutic regions having the same composition or differentcompositions and/or the same thickness or different thicknesses. As withthe microbeads shown in FIG. 51, individual pellets of the plurality canvary from one another in one or more of shape, polymer composition,concentration of therapeutic agent in the therapeutic region,concentration of the releasing agent in the control region, thickness ofthe control region, thickness of the therapeutic region, and any otherparameter that affect the release profile. As a result, the compositerelease profile of the plurality of pellets can be finely tuned toachieve the desired cumulative release of therapeutic agent to thetreatment site.

In various embodiments, the depot can be different sizes, for example,the depot may be a length of from about 0.4 mm to 100 mm and have adiameter or thickness of from about 0.01 to about 5 mm. In variousembodiments, the depot may have a layer thickness of from about 0.005 to5.0 mm, such as, for example, from 0.05 to 2.0 mm. In some embodiments,the shape may be a rectangular or square sheet having a ratio of widthto thickness in the range of 20 or greater, 25 or greater, 30 orgreater, 35 or greater, 40 or greater, 45 or greater, or 50 or greater.

In some embodiments, a thickness of the control region (a singlesub-control region or all sub-control regions combined) is less than orequal to 1/10, 1/15, 1/20, 1/25, 1/30, 1/35, 1/40, 1/45, 1/50, 1/75, or1/100 of a thickness of the therapeutic region. In some embodiments, thedepot 100 has a width and a thickness, and a ratio of the width to thethickness is 21 or greater. In some embodiments, the ratio is 22 orgreater, 23 or greater, 24 or greater, 25 or greater, 26 or greater, 27or greater, 28 or greater, 29 or greater, 30 or greater, 35 or greater,40 or greater, 45 or greater, or 50 or greater. In some embodiments, thedepot 100 has a surface area and a volume, and a ratio of the surfacearea to volume is at least 1, at least 1.5, at least 2, at least 2.5, orat least 3.

I. EXAMPLE METHODS OF MANUFACTURE

The depots of the present technology may be constructed using variouscombinations of bioresorbable polymer layers, wherein these layers mayinclude therapeutic agents, releasing agents, delayed release agents,etc., in varying combinations and concentrations in order to meet therequirements of the intended clinical application(s). In someembodiments, the polymer regions or layers may be constructed using anynumber of known techniques to form a multilayer film of a particularconstruction. For example, a bioresorbable polymer and a therapeuticagent can be solubilized and then applied to the film via spray coating,dip coating, solvent casting, and the like. In an alternativeembodiment, a polymer layer for use as a control region and/or atherapeutic region can be constructed from electrospun nanofibers.

The depots 100 described herein may be constructed by placingtherapeutic regions (and/or sub-regions) and/or control regions (and/orsub-regions) on top of one another in a desired order and heatcompressing the resulting multilayer configuration to bond the layerstogether. Heat compression may be accomplished using any suitableapparatus known in the art. In one embodiment, the heat compressionprocess consists of utilizing a heat compressor (Kun Shan RebigHydraulic Equipment Co. Ltd., China), and heat compressing the stackedassembly of therapeutic 200 and/or control regions 300 at a temperaturethat is above room temperature (e.g., at least 30° C., 35° C., 40° C.,45° C., 50° C., 55° C., 60° C., 65° C., 70° C., 75° C., 80° C., 85° C.,90° C., 95° C., 100° C., 105° C., 110° C., 115° C., or 120° C., etc.)and a pressure of from about 0.01 MPa to about 1.0 MPa, or about 0.10MPa to about 0.8 MPa, or about 0.2 MPa to about 0.6 MPa. The inventorshave discovered that heating the therapeutic and control regions duringcompression (separately or after stacking) increases the therapeuticagent density in the depot 100. The inventors have also discovered thatheat compression at lower pressures enable higher drug densities.

Depending on the therapeutic dosage needs, anatomical targets, etc., thedepot 100 can be processed, shaped and otherwise engineered to produceform factors that can be administered to the patient by implantation inthe body by a clinical practitioner. For example, various configurationsof the film may be achieved by using a jig with a pre-shaped cutout,hand cutting the desired shape or both. Some of the form factorsproducible from the multilayer film for implantation into the bodyinclude: strips, ribbons, hooks, rods, tubes, patches, corkscrew-formedribbons, partial or full rings, nails, screws, tacks, rivets, threads,tapes, woven forms, t-shaped anchors, staples, discs, pillows, balloons,braids, tapered forms, wedge forms, chisel forms, castellated forms,stent structures, suture buttresses, coil springs, and sponges. Asdescribed below with respect to FIG. 52C, in some embodiments apellet-like or mini-cylindrical depot 100 can be punched or otherwisecut out of a sheet of a multilayer film. A depot 100 may also beprocessed into a component of the form factors mentioned above. Forexample, the depot 100 could be rolled and incorporated into tubes,screws tacks or the like. In the case of woven embodiments, the depot100 may be incorporated into a multi-layer woven film wherein some ofthe filaments used are not the inventive device. In one example, thedepot 100 is interwoven with Dacron, polyethylene or the like.

In some embodiments, one or more depots 100 can be cut into a desiredshape or form factor using precision laser cutting. Various lasermodalities may be used, for example infrared lasers, near-infraredlasers, deep ultraviolet lasers, or other suitable lasers for cuttingdepots 100 to the desired configurations. Such laser cutting can usecontinuous or pulsed, and the operating parameters (e.g., intensity,frequency, polarization, etc.) may be selected to achieve the desiredcut. Using computer-controller laser-cutting can provide for a precise,repeatable manufacturing process that achieves consistent dimensions andrelease profiles. In some embodiments, the cut surfaces resulting fromthe laser-cut can be significantly smoother than those achieved using amechanical stamp, jig, or punch to cut depots from a sheet of amulti-layer film. In some instances, the smoother cut surfaces canprovide for improved release profiles, for example with more consistencyamong depots 100 manufactured according to this process.

In some embodiments, the therapeutic region 200 can be extruded into anelongated form (e.g., a cylindrical rod), after which the control region300 may be spray- or dip-coated over the extruded therapeutic region200. Portions of the extruded therapeutic region 200 may be masked toleave gaps in the control region 300, or alternatively portions of thecontrol region 300 may be removed via etching, scraping, or othertechniques to achieve any desired openings or thinning of the controlregion 300 in any desired portions. In some embodiments, an extrudedcylinder having a lumen extending therethrough can be selectively filledwith a therapeutic region 200 and/or a control region 300 along itslength to form an elongated depot 100.

In some embodiments, a therapeutic region 200 in the shape of acylindrical rod is formed by dissolving the therapeutic regioncomposition (e.g., a mixture of polymer(s) and therapeutic agent) intoacetone, and then loading the dissolved therapeutic region compositioninto a syringe (e.g., a 1 mL syringe) and attaching a needle thereto(e.g., a 19G needle). The therapeutic region solution is then injectedinto ethanol for polymer solidification. After waiting for the solutionto harden (e.g., approximately 90 seconds), the resulting rod can beremoved from the ethanol and air-dried. In another embodiment, thetherapeutic region composition can be injected into a cross-linkingsolution to solidify the polymer.

The therapeutic region 200 may be spray- or dip-coated with asurrounding control region 300. Alternatively, in some embodiments, thetherapeutic region 200 in elongated cylindrical form can be insertedinto an inner lumen of a coaxial needle. The coaxial needle can includean inner needle disposed coaxially within the lumen of an outer needle.In one example, the inner needle can have an inner diameter ofapproximately 0.84 mm and an outer diameter of approximately 1.24 mm,and the outer needle can have an inner diameter of approximately 1.6 mmand an outer diameter of approximately 2.11 mm, though these dimensionscan vary and be tailored to the desired dimensions of the therapeuticregion 200 and control region 300. A control region composite (e.g., amixture of polymer and releasing agent) can be dissolved in acetone, andthen loaded into a syringe (e.g., a 1 mL syringe). The control regionsolution is then injected through the outer needle, surrounding thecylindrical therapeutic region disposed within the inner needle. Theresulting depot 100 is a cylindrical form with a control region 300substantially uniformly surrounding the inner cylindrical therapeuticregion 200. In some embodiments, the resulting cylindrical form can besuitable for injecting using a needle, thereby providing for aconvenient mechanism to deliver the depot to any number of differenttreatment sites. In other embodiments, a coaxial needle having three ormore coaxial lumens can be used for the formation of multipletherapeutic and/or control regions, for example having a plurality ofdifferent therapeutic agents that can be configured to be releasedsequentially from the depot 100.

In some embodiments, an extruded depot 100 in the form an elongatedcolumnar structure (e.g., a cylindrical rod, strip, etc.) can be pincheddown at one or more positions along its length to be subdivided intodiscrete portions. For example, an elongated depot 100 may be pinchedsuch that the depot is completely severed into discrete sections, or toprovide a narrowed, weakened portion that can be susceptible to flexingand/or breaking.

FIG. 52C illustrates one method of manufacturing depots in the form ofpellets as shown in FIGS. 52A and 52B. A sheet including a plurality oflayered regions such as outer control regions 300 at least partiallysurrounding an inner therapeutic region 200 is provided. A punch 600with a hollow blade can be used to cut out individual pellets from thesheet, for example by pressing the punch 600 through the sheet along anaxis orthogonal to the surface of the sheet. In some embodiments, theresulting pellets each retain the layered regions of the sheet (e.g., atherapeutic region 200 sandwiched between first and second controlregions 300). In such embodiments, the resulting pellet can have atleast a portion of the therapeutic region 200 exposed through thecontrol region(s) 300, for example with lateral sides of the pellethaving exposed portions of the therapeutic region 200. Such exposedportions of the therapeutic region 200 can contribute to a higherinitial release rate of the therapeutic agent.

In some embodiments, the punch 600 is heated before cutting the pelletsfrom the sheet, for example by being heated in an oven to approximately80° C., or to a suitable temperature to at least partially melt ordeform the control region 300. The heated punch 600 can at leastpartially deform the top layer (e.g., partially melting the uppercontrol region 300) causing it to wrap around the lateral edges of thetherapeutic region 200. The resulting depot 100 may then take the formof a pellet 100 in which the inner therapeutic region 200 is completelyor substantially completely surrounded by the control region(s) 300. Insome embodiments, the motion of pressing the punch 600 can be varied toachieve the desired coverage of the control region(s) 300 over thetherapeutic region 200. For example, in some embodiments, the punch 600can be rotated while being pressed through the sheet, and in someembodiments the punch 600 can be moved more slowly or move quickly toallow varying degrees of deformation and flow of the control region(s)300. In other embodiments, the punch 600 is not heated before beingpressed through the sheet.

The dimensions of the depots 100 in the form of pellets ormini-cylinders can be controlled by varying the thickness of the sheetand by selecting the diameter or lumen cross-sectional dimensions of thepunch 600. In some embodiments, the sheet can have a thickness ofbetween about 0.5 and 2 mm (e.g., approximately 0.85 mm), and the punch600 can have a circular lumen with a diameter of between about 0.5 mmand about 3 mm (e.g., approximately 1 mm). In other embodiments, thepunch 600 can cut out depots 100 in other shapes, for example, square,rectangular, elliptical, star-shaped, wavy, irregular polygonal, or anyother suitable cross-sectional shape. In some embodiments, a wavy orjagged shape can provide a larger surface area for the resultingpellets, thereby increasing a rate of release of therapeutic agent fromthe pellets. In some embodiments, the resulting depots 100 in the formof pellets or mini-cylinders are insertable through a needle or othersuitable delivery shaft. For example, a plurality of approximatelypellets having 1 mm diameters may be loaded coaxially into a 17-gaugeneedle and inserted subcutaneously to a treatment site in a patient.Smaller pellet-like depots 100 could be inserted through even smallerneedles, for example 18- to 22-gauge needles. Such pellets ormini-cylinders can achieve a considerably high drug loading, asdescribed elsewhere herein, for example at least 50% by weight of thetherapeutic agent or more.

In some embodiments, microbead and/or pellet-like depots (e.g., as inFIGS. 51-52) can be formed by providing an elongated structure (e.g., acylindrical, columnar, or rod-shaped structure) having a therapeuticregion 200 at least partially surrounded by a control region 300, andthen cutting or otherwise dividing the structure into a plurality ofpellets, particles, or microbeads along its length.

II. EXAMPLES

The following examples are offered by way of illustration and not by wayof limitation.

Example 1

Preparation of bioresorbable polymer/drug films. Two depots of thepresent technology containing a high payload the local anestheticbupivacaine were prepared according to the following procedures.

Each of the sample depots consisted of a heat compressed, multi-layerfilm having the configuration shown in FIG. 5. The therapeutic regionconsisted of a single layer and was sandwiched between two inner controllayers (closest to the therapeutic layer, such as 302 b and 302 c inFIG. 5, and referred to as “Control Layer A” in Table 4 below) and twoouter control layers (farthest from therapeutic region, such as 302 aand 302 d in FIG. 5, and referred to as “Control Layer B” in Table 4).The constituents of the therapeutic region and the control region aredetailed in Table 4.

TABLE 4 Single layer Therapeutic Region PolymerPoly(L-lactide-co-glycolic-co-ε-caprolactone) (1760 mg) (Durect Corp,Birmingham) PLA to PGA to PCL ratio of from 90:5:5 to 60:30:10 ReleasingAgent Tween 20 (860 mg) (Sigma-Aldrich Pte Ltd; Singapore) Anestheticbupivacaine hydrochloride (3520 mg) (Xi'an Victory BiochemicalTechnology Co., Ltd.; Shaanxi, People's Republic of China)Anesthetic:Polymer 2:1 Releasing Agent:Polymer:Anesthetic 5:10:20Control Region Control Layer A innermost layer on top and bottom PolymerPLGACL (1056 mg) Releasing Agent Tween 20 (517 mg) Control Layer Boutermost layer on top and bottom Polymer PLGACL (1056 mg) ReleasingAgent Tween 20 (103 mg)

Therapeutic region components. The therapeutic region was prepared bycombining the polymer, releasing agent, anesthetic, and 3.15 mg ofacetone (Merck; Kenilworth, N.J.) in a glass vial and mixing thoroughly.The resulting blend was poured onto a flat plate and compressed multipletimes to form a thick film (about 1 mm thick) upon drying.

Control region components. The control region was prepared by combiningthe polymer, releasing agent, and 4.7 mg of acetone (Merck; Kenilworth,N.J.) in a glass vial and mixing thoroughly. The resulting blend waspoured onto a flat plate and drawn by a film applicator to form a thinfilm (<200 μm thickness) upon drying.

For the sample depot, the single layer therapeutic region and the fourlayers comprising the control region were aligned and compressed by aheat compressor. The thin film was cut to form a 25 mm×15 mm sample withoverall film thickness <1.2 mm.

in vitro drug release testing of bupivacaine depot. The purpose of thisprocedure was to measure the release of bupivacaine from a bioresorbablepolymer depot into a receiving fluid of 1×PBS. Each release experimentwas conducted in duplicate. The in vitro release procedure consisted ofplacing a known size of film into an apparatus containing the receivingfluid. The in vitro release apparatus consisted of a 200 mL glassbottle. A receiving fluid in the amount of 100 mL was added to eachsample bottle. During the release study, the apparatus was placed in awater bath maintained at 37±2° C. At predetermined intervals, samples ofthe receiving fluid were removed and analyzed for bupivacaineconcentration by UV-Visible Spectrophotometer.

FIG. 53 shows the drug release profile for the depots with effectivelyreduced initial burst effect and demonstrated a desirable consistentcontrolled release of drug.

Example 2A

Preparation of bioresorbable polymer/drug films. Two depots of thepresent technology comprising the local anesthetic bupivacaine wereprepared as described in Example 1, except the depots of the presentexample comprised two of the depots of Example 1 stacked on top of oneanother and heat compressed to form a new, thicker sample having anoverall film thickness of about 2 mm (for example, see the configurationshown in FIG. 6).

in vitro drug release testing of bupivacaine depot. in vitro drugrelease testing of the depots was performed as described in Example 1.

Release profiles. FIG. 54 shows the average cumulative dose profiles ofthe bupivacaine films. The graph shows controlled release of over 500hours with the initial 24-hour release of about 20%.

Example 2B

Preparation of bioresorbable polymer/drug films. Two depots of thepresent technology comprising the local anesthetic bupivacaine wereprepared as described in Example 1, except the depots of the presentexample comprised three of the depots of Example 1 stacked on top of oneanother and heat compressed to form a new, thicker sample having anoverall film thickness of about 3 mm (for example, see the configurationshown in FIG. 7).

In vitro drug release testing of bupivacaine depot. in vitro drugrelease testing of the depots was performed as described in Example 1.

Release profiles. FIG. 55 shows the average cumulative dose profiles ofthe bupivacaine films. The graph shows controlled release of over 500hours with the initial 24-hour release of about 20%.

Example 3

Preparation of bioresorbable polymer/drug films. Four depots of thepresent technology comprising the local anesthetic bupivacaine wereprepared as described below.

Each of the sample depots consisted of a heat compressed, multi-layerfilm formed of an inner depot similar to that shown in FIG. 5encapsulated by a different control region (described below). The innerdepot of each sample depot consisted of a therapeutic region (formed of10 heat-compressed therapeutic layers) sandwiched between two innercontrol layers (closest to the therapeutic region, such as 302 b and 302c in FIG. 5, and referred to as Control Layer A in Table 5 below) andtwo outer control layers (farthest from therapeutic region, such as 302a and 302 d in FIG. 5), and referred to as Control Layer B in Table 5).The constituents of the therapeutic region and the control region aredetailed in Table 5.

TABLE 5 10 heat-compressed microlayers Therapeutic Region PolymerPoly(L-lactide-co-ε-caprolactone)(PLCL) (Corbion; Lenexa, KS) having aPLA to PCL ratio of from 90:10 to 60:40 (880 mg) Releasing Agent Tween20 (440 mg) (Sigma-Aldrich Pte Ltd; Singapore) Anesthetic bupivacainehydrochloride (1760 mg) (Xi'an Victory Biochemical Technology Co., Ltd.;Shaanxi, People's Republic of China) DCM 13.33 g Anesthetic:Polymer 2:1Control Region Control Layer A Polymer PLCL (352 mg) Releasing AgentTween 20 (172 mg) DCM 5.3 g Control Layer B Polymer PLCL (352 mg)Releasing Agent Tween 20 (35 mg) DCM 5.3 g

Therapeutic region. The therapeutic region constituents (see Table 5above) were added to a glass vial and mixed thoroughly. The resultingblend was poured onto a flat plate and drawn by a film applicator toform a thin film upon drying (<200 μm thickness).

Control region. The control region constituents (see Table 5 above) wereadded to a glass vial and mixed thoroughly. The resulting blend waspoured onto a flat plate and drawn by a film applicator to form a thinfilm upon drying (<200 μm thickness).

For each sample film, 10 drug layers (each initially <200 μm thickness)and 4 control layers were aligned (Control B-Control A-10 therapeuticlayers-Control A-Control B) and compressed by a heat compressor (KunShan Rebig Hydraulic Equipment Co. Ltd.; People's Republic of China).The resulting thin film was cut to form a 20 mm×20 mm triangle samplewith an overall film thickness of <0.2 mm. The triangle samples werefurther aligned, and fully encapsulated, with (a) a Control Layer A onboth sides (i.e., two additional control layers), (b) a Control Layer Bon both sides (i.e., two additional control layers), (c) two of ControlLayer A on both sides (i.e., four additional control layers), (d) two ofControl Layer B on both sides (i.e., four additional control layers).The resulting assembly was then compressed by a heat compressor (KunShan Rebig Hydraulic Equipment Co. Ltd.; People's Republic of China).

in vitro drug release testing of bupivacaine depot. The purpose of thisprocedure was to measure the release of bupivacaine, from abioresorbable polymer depot into a receiving fluid of 1×PBS. Eachrelease experiment was conducted in duplicate. The in vitro releaseprocedure consisted of placing a known size of film into an apparatuscontaining the receiving fluid. The in vitro release apparatus consistedof either a 20 mL or a 100 mL glass bottle. A receiving fluid in theamount of 12 mL or 50 mL was added to each sample bottle. During therelease study, the apparatus was placed in a water bath maintained at37±2° C. At predetermined intervals, samples of the receiving fluid wereremoved and analyzed for bupivacaine concentration by a UV-VisibleSpectrophotometer.

Release profiles. FIG. 56 shows the average cumulative dose profiles ofthe bupivacaine films. The graph shows controlled release of over 1500hours for some of the configurations.

Example 4

Sample depots of the present technology were implanted subcutaneously inliving rabbits (one depot per rabbit). The depots were placed in asubcutaneous pocket.

Each of the sample depots consisted of a heat compressed, multi-layerfilm having the configuration shown in FIG. 5. The therapeutic regionconsisted of a single layer and was sandwiched between two inner controllayers (closest to the therapeutic layer, such as 302 b and 302 c inFIG. 5) and two outer control layers (farthest from therapeutic region,such as 302 a and 302 d in FIG. 5).

The present example tested two groups of depots, each utilizing adifferent polymer. The depots in Group A included Poly(DL-lactide-glycolide-ε-caprolactone) in a molar ratio of 60:30:10, andthe depots in Group B included Poly (DL-lactide-co-glycolide) in a molarratio of 50:50. Each group included a depot having a low, medium, orhigh dose of bupivacaine HCl.

For the depots of Group A, each inner control layer consisted of 3.9 mg,4.0 mg, or 4.7 mg of the polymer (for Low, Med, and High dose groups,respectively) and 1.9 mg, 2.0 mg, or 2.3 mg of a releasing agent(polysorbate 20) (for Low, Med, and High dose groups, respectively).Each outer control layer consisted of 5.3 mg, 5.5 mg, or 6.3 mg of thepolymer (for Low, Med, and High dose groups, respectively) and 1.9 mg,2.0 mg, or 2.3 mg of a releasing agent (polysorbate 20) (for Low, Med,and High dose groups, respectively).

For the depots of Group A, the therapeutic region consisted of 71.5 mg,152.6 mg, or 269 mg of the polymer (for Low, Med, and High dose groups,respectively), 34.9 mg, 74.6 mg, or 131.5 mg of a releasing agent(polysorbate 20) (for Low, Med, and High dose groups, respectively), and142.9 mg, 305.2 mg, or 538.1 mg of a local anesthetic (bupivacaine HCl).

For the depots of Group B, each inner control layer consisted of 4.7 mg,5.1 mg, or 5.3 mg of the polymer (for Low, Med, and High dose groups,respectively) and 2.3 mg, 2.5 mg, or 2.6 mg of a releasing agent(polysorbate 20) (for Low, Med, and High dose groups, respectively).Each outer control layer consisted of 6.4 mg, 6.9 mg, or 7.3 mg of thepolymer (for Low, Med, and High dose groups, respectively), and 0.6 mg,0.7 mg, or 0.7 mg of a releasing agent (polysorbate 20) (for Low, Med,and High dose groups, respectively).

For the depots of Group B, the therapeutic region consisted of 87.0 mg,171.1 mg, or 317.7 mg of the polymer (for Low, Med, and High dosegroups, respectively), 42.5 mg, 83.6 mg, or 155.2 mg of a releasingagent (polysorbate 20) (for Low, Med, and High dose groups,respectively), and 173.9 mg, 342.2 mg, or 635.4 mg of a local anesthetic(bupivacaine HCl).

Within each of Group A and Group B, the low dose depots were about 20mm×20 mm×<1 mm (e.g., 0.89 mm and 0.9 mm), the medium dose depots wereabout 20 mm×20 mm×<2 mm (e.g., 1.8 mm and 1.6 mm), and the high dosedepots were about 20 mm×20 mm×<3 mm (e.g., about 2.7 mm and about 2.8mm).

Blood draws for bupivacaine concentration analysis were collectedthrough Day 28.

Group A

The Group A depots were administered to 3 rabbits/dose group and PKsamples were collected to day 28. The semi-log plot of the group meandata for each dose is shown in FIG. 57. The product, regardless of dose,exhibits peak exposure within the first 72 hours and then a plateau ofexposure that is determined by the dose (the higher the dose the longerthe plateau) followed by more rapid terminal clearance. The release ofbupivacaine is rapid with a consistent similar profile for each rabbitwith moderate variability over the first 72 hours.

The in vitro pharmacokinetic (“PK”) profile for Group A is shown in FIG.57B. The half-life of the initial distribution phase through the first72-96 hours was generally consistent through the three dose strengths(implant sizes) and T_(max) occurred within the first 24 hours for allrabbits, with a median T_(max) between 4-8 hours. The peak exposure(C_(max)) for the high dose exhibited a low CV % of 17.6%. This datawould indicate a controlled initial rapid release of bupivacaine duringthe period of greatest discomfort post TKA surgery. The exposure profilewas stable from 72 hours through at least 436 hours. The terminal phasehalf-life started to exhibit the more innate half-life of bupivacaine,particularly in the high dose where the terminal phase t_(1/2) was 17.4hours. This would suggest that the depot had almost completely releasedthe drug by Day 21.

The high dose, Group A depot was consistent in average exposure from Day3 to Day 18, while the mid and low dose depots were consistent from Day3 to Day 14. There was not a significant difference in exposure betweenthe Mid and High dose groups from Day 3-14, while the Low dose wasapproximately half the exposure level during this time period.

Group B

Formulation 50:50 copolymer was administered to 3 rabbits/dose group andPK samples were collected to hour 672 (Day 28). The semi-log plot of thegroup mean data for each dose is presented in FIG. 57C. The product,regardless of dose, exhibits peak exposure within the first 72 hours andthen a gradual decline in exposure followed by a secondary fasterrelease coupled with a secondary peak in exposure at approximately Day19-21. After the secondary peak, bupivacaine exposure declined withdifferent rates dependent on dose (lower the dose the faster theclearance). FIG. 57C highlights the group mean (SD) and individualrabbits for Low Dose (126 mg) in Panel A, Mid Dose (252 mg) in Panel Band High Dose (420 mg) in Panel C through the first 96 hours. Therelease of bupivacaine is rapid with a consistent and similar profilefor each rabbit with moderate variability over the first 72 hours.

The in vitro pharmacokinetic profile is shown in FIG. 57D. The 50:50copolymer did not exhibit an initial distribution half-life like the 631terpolymer, however T_(max) occurred within the first 24 h for allrabbits, with a median T_(max) that was slightly further out in time,between 16-20 hours. The peak exposure (C_(max)) exhibited a very low CV% of 5.99%. This data would indicate a controlled initial rapid releaseof bupivacaine during the acute postoperative pain period (i.e., periodof greatest discomfort post TKA surgery) followed by a more gradualdecline in release rate through the subacute postoperative pain period,which is consistent with the presumed steady decline in pain during thatsame period. This release profile having the steady decline in releaserate during the acute postoperative pain period is in contrast with therelease rate of the 631 polymer formulation, where the release ratestates substantially constant throughout the postoperative pain period.

All three dose levels slowly decreased exposure over the Day 3 to Day 18time period.

Example 5

Two sample depots of the present technology were implanted in theintraarticular space of a knee joint of a living canine. The surgeonperformed a medial and lateral parapatellar arthrotomy to insert onesample depot in the medial gutter and one sample depot in the lateralgutter. The depots were anchored in place by 4-0 PDS II suture. Twocanines were the subject of the present study.

Each of the sample depots consisted of a heat compressed, multi-layerfilm having the configuration shown in FIG. 5. The therapeutic regionconsisted of a single layer and was sandwiched between two inner controllayers (closest to the therapeutic layer, such as 302 b and 302 c inFIG. 5) and two outer control layers (farthest from therapeutic region,such as 302 a and 302 d in FIG. 5). Each inner control layer consistedof 5.7 mg of a bioresorbable polymer (60:30:10 terpolymer Poly(DL-lactide-glycolide-ε-caprolactone)) and 2.8 mg of a releasing agent(polysorbate 20). Each outer control layer consisted of 7.7 mg of abioresorbable polymer (60:30:10 terpolymer Poly(DL-lactide-glycolide-ε-caprolactone)) and 0.8 mg of a releasing agent(polysorbate 20).

The therapeutic region comprised a single layer consisting of 118 mg ofa bioresorbable polymer (60:30:10 terpolymer Poly(DL-lactide-glycolide-ε-caprolactone)), 57.6 mg of a releasing agent(polysorbate 20), and 235.9 mg of a local anesthetic (bupivacaine HCl).

Each of the depots was about 15 mm×about 25 mm×about 1 mm.

Following implantation, the canines were evaluated at predeterminedintervals to determine the post-operative pharmacokinetic (PK) profileof bupivacaine in synovial fluid and blood plasma. For PK values ofbupivacaine in the blood plasma (i.e., representing systemic bupivacainelevels), blood was drawn at scheduled intervals after implantation ofthe depots. The PK results for the plasma fluid samples are shown atFIG. 58.

As shown in FIG. 58, the depot 100 released an initial, controlled burstover about the first three days, followed by a tapering release for theremaining 11 days.

Example 6

Three sample depots of the present technology were implanted in theintraarticular space of a knee joint of a living sheep. The surgeonperformed a medial and lateral parapatellar arthrotomy to insert onesample depot in the medial gutter and two sample depots in the lateralgutter. The lateral gutter depots were sutured side-by-side prior toimplantation to keep the depots in place relative to each other in thegutter. The depots were then anchored in place to the capsular tissue by4-0 PDS II suture.

Each of the sample depots consisted of a heat compressed, multi-layerfilm having the configuration shown in FIG. 5. The therapeutic regionconsisted of a single layer and was sandwiched between two inner controllayers (closest to the therapeutic layer, such as 302 b and 302 c inFIG. 5) and two outer control layers (farthest from therapeutic region,such as 302 a and 302 d in FIG. 5). Each inner control layer consistedof 5.3 mg of a bioresorbable polymer (Poly (DL-lactide-co-glycolide) ina molar ratio of 50:50)) and 2.6 mg of a releasing agent (polysorbate20). Each outer control layer consisted of 7.2 mg of a bioresorbablepolymer (Poly (DL-lactide-co-glycolide) in a molar ratio of 50:50)) and0.7 mg of a releasing agent (polysorbate 20).

The therapeutic region comprised a single layer consisting of 118.1 mgof a bioresorbable polymer (Poly (DL-lactide-co-glycolide) in a molarratio of 50:50), 57.7 mg of a releasing agent (polysorbate 20), and236.3 mg of a local anesthetic (bupivacaine HCl).

Each of the depots was about 15 mm×about 25 mm×about 1 mm.

Following implantation, the sheep was evaluated at 1, 4, 8, 15, and 30days to determine the post-operative pharmacokinetic (PK) profile ofbupivacaine in synovial fluid and blood plasma.

For PK values of bupivacaine in the blood plasma (i.e., representingsystemic bupivacaine levels), 1 mL of blood was drawn 1, 2, 4, 8, 12,16, 20, 24 and 48 hours after implantation of the depots, then every 48hours (at the same time as was drawn on previous days, +/−1 hr) in allanimals until day 28 prior to sacrifice. The PK results for the plasmafluid samples are shown in FIG. 59A. As shown, the systemic plasmabupivacaine concentration showed an initial, controlled burst over thefirst 2-4 days, followed by a tapering release for the remaining period.

For PK values of bupivacaine in the synovial fluid (i.e., representinglocal bupivacaine levels), a minimum of 0.5 mL of synovial fluid wasaspirated from the joint at 0 hours (i.e., just prior to surgery), 24hours, 96 hours, and 192 hours. The PK results for the synovial fluidsamples are shown in FIG. 59B. As shown, the local synovialconcentration showed an initial, controlled burst over the first 2-4days, followed by a tapering release for the remaining period.

FIG. 59C is a plot depicting the blood plasma bupivacaine concentrationversus the synovial bupivacaine concentration over time. As demonstratedin FIG. 59C, the PK values are illustrative of a release profileachieved in prior in vitro and in vivo studies, wherein the initial,controlled burst over the first 2-4 days provides a substantial dosageof bupivacaine during the acute postoperative pain period and thetapering release that follows provides a therapeutic dosage during thesubacute postoperative pain period. As shown, local bupivacaine levelswere an order of magnitude greater than systemic bupivacaine levels.Achieving a high local concentration of bupivacaine withoutcorrespondingly high systemic levels allows for optimized analgesiawithout the risk of systemic toxicity.

Example 7

The purpose of this study was to evaluate the surgical procedure anddrug delivery characteristics of two formulations of the depots of thepresent technology.

Samples

Two polymer systems were evaluated in this study. The first polymersystem (FT1-B) was constructed from a terpolymer of PLA, PGA andpolycaprolactone (PCL) in ratios of 6:3:1; the second polymer system(FT1-C) was constructed from a copolymer of 50:50 PLA and PGA (PLGA).All polymers in both systems are shown to be biocompatible in otherdevices and clinical applications. Both of these polymer systems containthe D-lactate exogenous stereoisomer, allowing for quantitative analysisin vivo. Additional details on the samples are shown in Tables 1 and 2of FIGS. 60A and 60B, respectively.

Five to six depot samples per group were implanted in the intraarticularspace of a knee joint of living sheep, all without sutures.

Each of the sample depots consisted of a heat-compressed, multi-layerfilm having the configuration shown in FIG. 5. The therapeutic regionconsisted of a single layer and was sandwiched between two inner controllayers (closest to the therapeutic layer, such as 302 b and 302 c inFIG. 5) and two outer control layers (farthest from therapeutic region,such as 302 a and 302 d in FIG. 5). For the FT1-B samples, each innerand outer control layer consisted of the 6:3:1 polymer mixed with Tween20 (a releasing agent). For the FT1-C samples, each inner and outercontrol layer consisted of the PLGA polymer mixed with Tween 20.

For the FT1-B samples, the therapeutic region consisted of Tween 20, the6:3:1 polymer, and bupivacaine HCl in a ratio of about 1:10:20. For theFT1-C samples, the therapeutic region consisted of Tween 20, the PLGApolymer, and bupivacaine HCl in a ratio of about 1:10:20.

Each of the depots was about 26 mm×about 16 mm×about 1 mm.

Results and Discussion

Blood draws for bupivacaine concentration analysis were collected priorto implantation through Day 30 post implantation. Blood samples weretested for bupivacaine levels (LLOQ=0.2 ng/mL). The bupivacaine releaseprofiles in blood plasma are summarized in FIG. 60C. Synovial fluid wasalso collected for bupivacaine level analysis. Bupivacaine levels insynovial fluid are summarized in FIG. 60D.

This study demonstrated that the depot prototypes release bupivacaineinto systemic circulation at safe exposure levels over 30 days afterplacement of up to 6 depots in sheep. Both depot prototypes demonstratedthe ability the sustain bupivacaine release for at least 14 days insheep.

A delay in the release of bupivacaine was observed in the FT1-B animal18109 (see FIG. 60B). The sample depots are designed to have a lag inbupivacaine release to limit toxic exposure immediately after surgery asbupivacaine or ropivacaine is administrated during the surgicalprocedure. Preferably, the lag in bupivacaine release should be at least8 hours.

FIG. 60E shows the average daily AUC for FT1-B and FT1-C from 0 to 72hours and from 3 to 14 days. The FT1-B animal 180109 demonstrated higherdaily AUC from day 3 to day 14 compared to the other two animals.

As shown in FIG. 60F, the concentration of bupivacaine in synovial fluidwas approximately 1000 times higher than in plasma for all animals. Thissupports a four compartment PK model where the articular capsulefunctions as a separate compartment due to its low vascularization.

This study demonstrated that the depot prototypes release bupivacaine ata safe level over 30 days after the placement of up to six depots insheep. The PK parameters from both the synovial fluid and blood plasmashowed that the sample depots were able to sustain bupivacaine deliveryfor more than 14 days. There was no evidence of dose dumping. Plasmamaximum concentration levels were approximately one order of magnitudebelow the generally regarded as safe level of 1,000 ng/mL (HED˜800-1,150 mg). The synovial fluid levels reflecting local bupivacaineconcentration in the knee capsule were approximately 3-4 orders ofmagnitude greater than the plasma levels.

Example 8

The purpose of this study was to evaluate the surgical procedure anddrug delivery characteristics of two formulations of the depots of thepresent technology.

Samples

Two polymer systems were evaluated in this study. The first polymersystem (FT1-B) was constructed from a terpolymer of PLA, PGA andpolycaprolactone (PCL) in ratios of 6:3:1; the second polymer system(FT1-C) was constructed from a copolymer of 50:50 PLA and PGA (PLGA).Additional details on the samples are shown in Table 6 below.

TABLE 6 Formulation Dose HED N P(DL)LA − PGA-PCL 825 mg 824 mg n = 3(6:3:1), T = 7 d P(DL)LA − PGA-PCL 921 mg 933 mg n = 3 (6:3:1), T = 45 dP(DL)LA − PGA-PCL 921 mg 933 mg n = 3 (6:3:1), T = 90 d P(DL)LA − PGA(1:1), 951 mg 948 mg n = 3 T = 7 d P(DL)LA − PGA (1:1), 1119 mg 1149 mgn = 3 T = 45 d P(DL)LA − PGA (1:1), 1119 mg 1149 mg n = 3 T = 90 d

The sample depots were sutured into the knee capsule of living sheep.

Each of the sample depots consisted of a heat-compressed, multi-layerfilm having the configuration shown in FIG. 4. The therapeutic regionconsisted of a single layer and was sandwiched between two controllayers. For the FT1-B samples, each control layer consisted of the 6:3:1polymer mixed with Tween 20 (a releasing agent) in a ratio of 1:2. Forthe FT1-C samples, each inner control layer consisted of the PLGApolymer mixed with Tween 20 in a ratio of 1:2.

For the FT1-B samples, the therapeutic region consisted of Tween 20, the6:3:1 polymer, and bupivacaine HCl in a ratio of about 1:10:20. For theFT1-C samples, the therapeutic region consisted of Tween 20, the PLGApolymer, and bupivacaine HCl in a ratio of about 1:10:20.

Each of the depots was about 26 mm×about 16 mm×about 1 mm.

Results and Discussion

Blood draws for bupivacaine concentration analysis were collected priorto implantation through Day 30 post implantation. Blood samples weretested for bupivacaine levels (LLOQ=0.2 ng/mL). The bupivacaine releaseprofiles in blood plasma are summarized in FIG. 61A. Synovial fluid wasalso collected for bupivacaine level analysis. Bupivacaine levels insynovial fluid are summarized in FIG. 61B.

This study demonstrated that the depot prototypes release bupivacaineinto systemic circulation at safe exposure levels over 30 days afterplacement of multiple depots in sheep. Both depot formulationsdemonstrated the ability the sustain bupivacaine release for at least 14days in sheep. There was no evidence of dose dumping. Plasma maximumconcentration levels were approximately 1 order of magnitude below thegenerally regarded as safe level of 1,000 ng/mL (HED ˜800-1,150 mg). Thesynovial fluid levels reflecting local bupivacaine concentration in theknee capsule were approximately 3-4 orders of magnitude greater than theplasma levels. Both FT1-B and FT1-C formulations had similar releaseprofiles in plasma and synovial fluid.

III. SELECTED SYSTEMS AND METHODS FOR TREATING POSTOPERATIVE PAINASSOCIATED WITH ORTHOPEDIC SURGERY

The depots 100 of the present technology may be used to treat a varietyof orthopedic injuries or diseases depending upon the nature of thetherapeutic agent delivered as described above. The therapeutic agentmay be delivered to specific areas of the patient's body depending uponthe medical condition being treated. The depots 100 of the presenttechnology may be positioned in vivo proximate to the target tissue(i.e., bone, soft tissue, etc.) in the patient's body to provide acontrolled, sustained release of a therapeutic agent for the treatmentof a particular condition. This implantation may be associated with asurgery or intervention for acutely treating the particular condition,whereby the depot enables chronic, sustained pharmacological treatmentfollowing completion of the surgery or intervention. The depot may be astandalone element, or may be coupled to or integrated as part of animplantable device or prosthesis associated with the intervention orsurgery.

The amount of the therapeutic agent that will be effective in a patientin need thereof will depend on the specific nature of the condition, andcan be determined by standard clinical techniques known in the art. Inaddition, in vitro or in vivo assays may optionally be employed to helpidentify optimal dosage ranges. The specific dose level for anyparticular individual will depend upon a variety of factors includingthe activity of the drug, the age, body weight, general physical andmental health, genetic factors, environmental influences, sex, diet,time of administration, location of administration, rate of excretion,and the severity of the particular problem being treated.

Some aspects of the present technology include a system comprising aplurality of depots (each of which could be any of the depots describedherein) provided for implantation by a clinical practitioner. In thissystem, each depot may be configured for controlled release oftherapeutic agent to tissue proximate to the implantation site of thedepot. The depots in the system may be identical or may vary in severalrespects (e.g., form factor, therapeutic agent, release profile, etc.).For example, the system may be comprised of a depot having a releaseprofile that provides for an immediate release of therapeutic agent andother depots comprised of a depot having a release profile that providesfor a delayed release of therapeutic agent.

Many depots of the present technology are configured to be implanted ata surgical site to treat postoperative pain at or near the site. As usedherein, the term “pain” includes nociception and the sensation of pain,both of which can be assessed objectively and subjectively, using painscores and other methods well-known in the art, such as opioid usage. Invarious embodiments, pain may include allodynia (e.g., increasedresponse to a normally non-noxious stimulus) or hyperalgesia (e.g.,increased response to a normally noxious or unpleasant stimulus), whichcan in turn be thermal or mechanical (tactile) in nature. In someembodiments, pain is characterized by thermal sensitivity, mechanicalsensitivity and/or resting pain. In other embodiments, pain comprisesmechanically-induced pain or resting pain. In still other embodiments,the pain comprises resting pain. The pain can be primary or secondarypain, as is well-known in the art. Exemplary types of pain reducible,preventable or treatable by the methods and compositions disclosedherein include, without limitation, include post-operative pain, forexample, from the back in the lumbar regions (lower back pain) orcervical region (neck pain), leg pain, radicular pain (experienced inthe lower back and leg from lumbar surgery in the neck and arm fromcervical surgery), or abdominal pain from abdominal surgery, andneuropathic pain of the arm, neck, back, lower back, leg, and relatedpain distributions resulting from disk or spine surgery. Neuropathicpain may include pain arising from surgery to the nerve root, dorsalroot ganglion, or peripheral nerve.

In various embodiments, the pain results from “post-surgical pain” or“post-operative pain” or “surgery-induced pain”, which are used hereininterchangeably, and refer to pain arising in the recovery period ofseconds, minutes, hours, days or weeks following a surgical procedure(e.g., hernia repair, orthopedic or spine surgery, etc.). Surgicalprocedures include any procedure that penetrates beneath the skin andcauses pain and/or inflammation to the patient. Surgical procedure alsoincludes arthroscopic surgery, an excision of a mass, spinal fusion,thoracic, cervical, or lumbar surgery, pelvic surgery or a combinationthereof.

FIGS. 62A and 62B illustrate common locations within a patient that maybe sites where surgery is conducted and locations where the depots ofthe present technology can be administered. It will be recognized thatthe locations illustrated in FIGS. 62A and 62B are merely exemplary ofthe many different locations within a patient where a surgery may takeplace. For example, surgery may be required at a patient's knees, hips,upper extremities, lower extremities, neck, spine, shoulders, abdomenand pelvic region. FIG. 63 is a table showing common surgical proceduresfor which the depots 100 of the present technology may be utilized fortreating postoperative pain.

Many embodiments of the present technology include one or more depots,having the same or different configuration and/or dosing, that areconfigured to be positioned at or near a surgical site of a knee jointto treat pain associated with a total knee replacement surgery. Aspreviously described, the depots of the present technology may be solid,self-supporting, flexible thin films that is structurally capable ofbeing handled by a clinician during the normal course of a surgerywithout breaking into multiple pieces and/or losing its general shape.This way, the clinician may position one or more of the depots atvarious locations at or near the intracapsular and/or extracapsularspace of the knee joint, as necessary to address a particular patient'sneeds and/or to target particular nerves innervating the knee.

FIGS. 64A-64C, for example, are front, lateral, and medial views of ahuman knee, showing the location of the nerves innervating the extra-and intracapsular portion of a knee joint. In some embodiments, thedepots may be implanted adjacent to one or more nerves (such as thenerves shown in FIGS. 64A-64C) innervating the knee.

In some instances, it may be beneficial to position one or more of thedepots within the joint capsule. For example, FIG. 65A is a splayed viewof a human knee exposing the intracapsular space and identifyingpotential locations for positioning one or more depots, and FIG. 65B isa splayed view of a human knee exposing the intracapsular space andshowing several depots 100 positioned within for treating postoperativepain. As shown in FIGS. 65A and 65B, in some instances, one or moredepots may be positioned at or near the suprapatellar pouch SPP,specifically under the periosteum and attached to the quadriceps tendon.Additional areas for placement of one or more depots 100 may includegenerally the medial and lateral gutters MG, LG (including optionalfixation to tissue at the medial or lateral side of the respectivegutter), on the femur F, on the tibia T (e.g., posterior attachment tothe tibial plateau, at or near the anterior tibia to anesthetizeinfrapatellar branches of the saphenous nerve). In some embodiments, oneor more depots may be positioned adjacent to at least one of a posteriorcapsule PC of the knee, a superior region of the patella P, and/or thearthrotomy incision into the knee capsule. In some embodiments, one ormore depots 100 may be positioned at or near the saphenous nerve, theadductor canal, and/or the femoral nerve. In some embodiments, one ormore of the depots may be configured to be positioned at or near aninfrapatellar branch of the saphenous nerve, one or more genicularnerves of the knee, a superior region of the patella P. It may bedesirable to position the depot within the knee capsule but away fromany articulating portions of the knee joint itself.

In some embodiments, one or more of the depots 100 may be configured tobe positioned at or near one or more nerves innervating an anterior kneecapsule. For example, the depots 100 may be configured to be positionedat or near a superolateral genicular branch from the vastus lateralis, asuperomedial genicular branch from the vastus medialis, a medial(retinacular) genicular branch from the vastus intermedius, aninferolateral genicular branch from the common peroneal nerve, aninferomedial genicular branch from the saphenous nerve, and/or a lateral(retinacular) genicular branch from the common peroneal nerve.

Instead of or in addition to the placement of depots within theintracapsular space, one or more depots may be placed at anextracapsular position. FIGS. 66A and 66B, for example, show anteriorand posterior views, respectively, of the nerves as positioned at anextracapsular location. In some embodiments, the depots may be implantedadjacent to one or more extracapsular nerves (such as the nerves shownin FIGS. 66A and 66B). As shown in FIG. 67, in some embodiments one ormore depots 100 may be positioned along or adjacent the subcutaneousskin incision.

In some embodiments, the system includes a first depot (or plurality ofdepots) and a second depot (or plurality of depots), all of which areconfigured to be implanted at or near the knee joint. The first depot(s)may have the same or different release profile, rate of release,therapeutic agent (such as non-anesthetic analgesics, NSAIDs,antibiotics, etc.), duration of release, size, shape, configuration,total payload, etc. as the second depot(s).

So as not to interfere or overlap with a peripheral nerve blockadministered perioperatively to the patient, one or more of the depotsmay optionally include a delay release capability for 6 to 24 hoursfollowing implantation. In some embodiments, one or more depots placedin the adductor canal and knee capsule may be configured to have a delayin the release of therapeutic agent that may exceed 24 hours.

The depots 100 disclosed herein may be used to treat postoperative painassociated with other knee surgeries. For example, one or more depotsmay be used to treat postoperative pain associated with an ACL repairsurgery, a medial collateral ligament (“MCL”) surgery, and/or aposterior cruciate ligament (“PCL”) surgery. For ACL repair, one or moredepots may be positioned to delivery analgesic the femoral and/orsciatic nerves, while for PCL repair surgery, one or more depots may bepositioned parasacral to deliver analgesic to the sciatic nerve. The oneor more depots may be used to treat postoperative pain associated with apartial knee replacement surgery, total knee replacement surgery, and/ora revision surgery of a knee replacement surgery. In such procedures,one or more depots can be placed contiguous to the joint or repair siteto provide a local block, or else may suitably positioned to provide aregional block by delivering an analgesic to one or more of the femoralnerve or the sciatic nerve, for example via placement in the adductorcanal.

In addition to the knee-related surgeries described above, embodimentsof the depots disclosed herein can be used to treat postoperative painassociated with other orthopedic surgeries as described in more detailbelow and as summarized in part in FIG. 62. Examples include surgicalprocedures involving the ankle, hip, shoulder, wrist, hand, spine, legs,or arms. For at least some of these surgical procedures, analgesic canbe provided to deliver a local block or a regional block to treatpostoperative pain. For a local block, one or more depots can beattached under direct vision in open surgery, for example during jointarthroplasty, open reduction and internal fixation (ORIF) surgery,ligament reconstruction, etc. In such procedures involving a joint, oneor more depots can be positioned at the joint capsule (e.g., at or nearthe intracapsular and/or extracapsular space of the joint) or adjacentsoft tissues spaced apart from articulating surfaces to avoid the depotinterfering with joint movement or being damaged by contact witharticulating surfaces. In cases involving fracture repair or ligamentrepair, one or more depots can be positioned at or adjacent to therepair site to provide a local block. For a regional block, one or moredepots can be deposited at a treatment site adjacent to the target nervevia ultrasound guidance using a blunt trocar catheter or other suitableinstrument. In at least some embodiments, it can be beneficial tocombine delivery of analgesic or other therapeutic agents via thedepot(s) with delivery of NSAIDs, a long-acting narcotic deliveredpre-operatively, and/or acetaminophen. The sustained, controlled,release of an analgesic via the one or more depots may work in concertwith these other therapeutic agents to provide a reduction inpostoperative pain associated with orthopedic and other surgicalprocedures.

In one example, one or more depots as described herein can be used totreat postoperative pain associated with foot and ankle surgeries suchas ankle arthroplasty (including ankle revision, ankle replacement, andtotal ankle replacement), ankle fusion, ligament reconstruction,corrective osteotomies (e.g., bunionectomy, pes planus surgery), or openreduction and internal fixation (ORIF) of ankle or foot fractures. Intreating postoperative pain associated with such surgeries, one or moredepots can be configured and positioned adjacent to the joint or repairsite to provide a local block. Additionally or alternatively, one ormore depots can be placed parasacral or at another suitable location totarget one or more of the subgluteal sciatic nerve, popliteal sciaticnerve, deep peroneal nerve, or the superficial peroneal nerve. In someembodiments, depots positioned to treat postoperative pain associatedwith ankle or foot surgeries can have a release profile configured todeliver therapeutically beneficial levels of analgesic for a period ofbetween 3-7 days.

In another example, one or more depots as described herein can be usedto treat postoperative pain associated with hip surgeries such as hiparthroplasty (including hip revision, partial hip replacement, and totalhip replacement) or open reduction and internal fixation (ORIF) of hipfactures. In treating postoperative pain associated with such surgeries,one or more depots can be configured and positioned adjacent to thejoint or repair site to provide a local block. Additionally oralternatively, a regional block can be provided by placing depots in thepsoas compartment, lumbar paravertebral space, fascia iliaca, or othersuitable location to target one or more of the lumbar plexus, sacralplexus, femoral nerve, sciatic nerve, superior gluteal nerve, orobturator nerve. In some embodiments, it may be beneficial to secure theone or more depot(s) (e.g., using a fixation mechanism as describedherein) to maintain an anterior position of the depot, therebypreventing or reducing exposure of analgesic to motor nerves (e.g.,sciatic or femoral nerves). In some embodiments, depots positioned totreat postoperative pain associated with hip surgeries can have arelease profile configured to deliver therapeutically beneficial levelsof analgesic for a period of 5-7 or 7-10 days depending on theparticular surgical procedure.

Post-operative pain associated with shoulder and upper-arm surgeries canlikewise be treated using one or more depots as disclosed herein.Examples of such surgeries include shoulder arthroplasty (includingshoulder revision, partial shoulder replacement, and total shoulderreplacement), upper-arm fracture repair (scapular, humerus),ligament/tendon repair (e.g., rotator cuff, labrum, biceps, etc.), oropen reduction and internal fixation (ORIF) of fractures of the shoulderor upper arm. In treating postoperative pain associated with suchsurgeries, one or more depots can be configured and positioned adjacentto the joint or repair site to provide a local block. Additionally oralternatively, one or more depots can be configured and positioned totarget the brachial plexus by placing one or more depots in the cervicalparavertebral space, interscalene, or supraclavicular space. In someembodiments, interscalene placement of the depots can avoid exposure ofanalgesic to native cartilage, thereby reducing the risk ofchondrotoxicity. In some embodiments, depots positioned to treatpostoperative pain associated with shoulder or upper-arm relatedsurgeries can have a release profile configured to delivertherapeutically beneficial levels of analgesic for a period of 3-7 days.

In another example, one or more depots as described herein can be usedto treat postoperative pain associated with elbow surgeries such aselbow arthroplasty (including elbow revision, partial elbow replacement,and total elbow replacement), ligament reconstruction, or open reductionand internal fixation (ORIF) of fractures of the elbow. In treatingpostoperative pain associated with such surgeries, one or more depotscan be positioned adjacent to the joint or repair site to provide alocal block. Additionally or alternatively, one or more depots can beconfigured and positioned to target the brachial plexus nerves, forexample by being placed at or near the cervical paravertebral space,infraclavicular, or axillary position, or other suitable location. Insome embodiments, depots positioned to treat postoperative painassociated with elbow surgeries can have a release profile configured todeliver therapeutically beneficial levels of analgesic for a period of3-7 days.

Post-operative pain associated with wrist and hand surgeries can also betreated using one or more depots as described herein. Examples of wristand hand surgeries include wrist arthroplasty (including wrist revision,partial wrist replacement, and total wrist replacement), wrist fusion,and open reduction and internal fixation (ORIF) of fractures of thewrist. In treating postoperative pain associated with such surgeries,one or more depots can be configured and positioned adjacent to thewrist joint or repair site to provide a local block. Additionally oralternatively, one or more depots can be configured and positioned totarget the target the ulnar, median, radial, and cutaneous forearmnerves, for example via placement at the antecubital fossa, cervicalparavertebral space, infraclavicular, or axillary position. In someembodiments, depots positioned to treat postoperative pain associatedwith wrist and hand surgeries can have a release profile configured todeliver therapeutically beneficial levels of analgesic for a period of3-7 days.

The depots disclosed herein may likewise be used to treat postoperativepain from other orthopedic surgeries. For example, post-operative painassociated with spinal fusion can be treated via placement of one ormore depots subcutaneously or in the paravertebral space. In treatmentof post-operative pain associated with fibular fracture repair, one ormore depots can be configured and placed to target the sciatic nerveand/or the popliteal sciatic nerve, for example being placed parasacral.Various other placements and configurations are possible to providetherapeutic relief from post-operative pain associated with orthopedicsurgical procedures.

The efficacy of the depots 100 of the present technology in providingpostoperative pain relief may be evaluated by several metrics, such aspain score, quality of recovery, opioid consumption and related sideeffects, and functional assessments such as range of motion testing, theWestern Ontario and McMaster Universities Osteoarthritis (WOMAC) Index,and the Knee Injury and Osteoarthritis Outcome Score (KOOS).

The WOMAC Index is a widely used, proprietary set of standardizedquestionnaires used by health professionals to evaluate the condition ofpatients with joint pain from a variety of sources. The WOMAC measuresfive items for pain (score range 0-20), two for stiffness (score range0-8), and 17 for functional limitation (score range 0-68). Physicalfunctioning questions cover everyday activities such as stair use,standing up from a sitting or lying position, standing, bending,walking, getting in and out of a car, shopping, putting on or taking offsocks, lying in bed, getting in or out of a bath, sitting, and heavy andlight household duties. The questions on the WOMAC are a subset of thequestions of the Hip disability and Osteoarthritis Outcome score (HOOS).Thus, a HOOS survey may also be used to determine a WOMAC score.

Some embodiments of the present technology include a method for treatinga patient suffering from postsurgical pain at an anatomical region ofthe patient's body. The pain may be associated with a surgery at or nearthe anatomical region. In some aspects of the disclosure, the method mayinclude improving a WOMAC index total score of the patient by implantingone or more of the depots 100 disclosed herein at a surgical site at theanatomical region. The method may include improving a WOMAC index painsub-score, stiffness sub-score, and/or physical function sub-score. TheWOMAC index total score and/or one or more of the sub-scores may beevaluated at set time intervals (weekly, monthly, bi-monthly, etc.) andcompared to the patient's previous scores, the patient's pre-operativescore, and/or the score of a patient of similar age, fitness, and healththat underwent the same surgery but was not treated with one of thedepots 100 of the present technology.

The KOOS was developed as an extension of the WOMAC Index with thepurpose of evaluating short-term and long-term symptoms and function insubjects with knee injury and osteoarthritis. The KOOS holds fiveseparately scored subscales: pain, other symptoms, function in dailyliving (ADL), function in sport and recreation (sport/rec), andknee-related quality of life (QOL). The KOOS has been validated forseveral orthopaedic interventions such as anterior cruciate ligamentreconstruction, meniscectomy and total knee replacement. The effect sizeis generally largest for the subscale QOL followed by the subscale pain.

In some aspects of the disclosure, the method may include improving aKOOS score of the patient by implanting one or more of the depots 100disclosed herein at a surgical site at the anatomical region. The methodmay include improving a KOOS sub-score, including at least one of pain,other symptoms, function in daily living (ADL), function in sport andrecreation (sport/rec), and/or knee-related quality of life (QOL). TheKOOS score and/or one or more of the sub-scores may be evaluated at settime intervals (weekly, monthly, bi-monthly, etc.) and compared to thepatient's previous scores, the patient's pre-operative score, and/or thescore of a patient of similar age, fitness, and health that underwentthe same surgery but was not treated with one of the depots 100 of thepresent technology.

In some embodiments, depots 100 of the present technology can utilizeregional procedure for controlling pain following TKA. Such procedurescan include local anesthetic infiltration between the popliteal arteryand capsule of the knee (IPACK) block. An IPACK block proceduretypically involves scanning the popliteal fossa using a probe proximalthe popliteal crease, and injecting an analgesic (e.g., 20-mL 0.25%ropivacaine) between the patient's popliteal artery and femur. Unlikeother known procedures (e.g., adductor canal block (ACB) and femoralnerve catheter (FNC) block) for treating postoperative pain followingTKA, IPACK block targets only the terminal branches of the sciaticnerve. In doing so, analgesia and/or other therapeutic agents can beprovided to the posterior knee region without causing distal neurologicdeficits. In some embodiments, depots 100 of the present technology canbe implanted using a combination of the IPACK block procedure and theACB or FNC block procedures. For example, patients may preoperativelyreceive one or more depots 100 utilizing an FNC block, and then receiveone or more additional depots 100 utilizing a post-operative IPACKblock. Utilizing the IPACK block procedure with depots 100 of thepresent technology can advantageously provide adequate analgesiafollowing TKA, promote improved physical therapy performance, reduce theincident of foot drop, reduce opioid consumption, and better controlposterior knee pain following TKA, e.g., relative to ACB, FNC block, orother known techniques for pain management following TKA, often allowingfor earlier hospital discharge.

IV. SELECTED SYSTEMS AND METHODS FOR TREATING POSTOPERATIVE PAINASSOCIATED WITH NON-ORTHOPEDIC SURGERY

The depots 100 of the present technology may be used to treat a varietyof medical conditions depending upon the nature of the therapeutic agentdelivered as described above. The therapeutic agent may be delivered tospecific areas of the patient's body depending upon the medicalcondition being treated. The depots 100 of the present technology may bepositioned in vivo proximate to the target tissue in the patient's bodyto provide a controlled, sustained release of a therapeutic agent forthe treatment of a particular condition. This implantation may beassociated with a surgery or intervention for acutely treating theparticular condition, whereby the depot enables chronic, sustainedpharmacological treatment following completion of the surgery orintervention. The depot 100 may be a standalone element, or may becoupled to or integrated as part of an implantable device or prosthesisassociated with the intervention or surgery.

The amount of the therapeutic agent that will be effective in a patientin need thereof will depend on the specific nature of the condition, andcan be determined by standard clinical techniques known in the art. Inaddition, in vitro or in vivo assays may optionally be employed to helpidentify optimal dosage ranges. The specific dose level for anyparticular individual will depend upon a variety of factors includingthe activity of the drug, the age, body weight, general physical andmental health, genetic factors, environmental influences, sex, diet,time of administration, location of administration, rate of excretion,and the severity of the particular problem being treated.

Some aspects of the present technology include a system comprising aplurality of depots (each of which could be any of the depots describedherein) provided for implantation by a clinical practitioner. In thissystem, each depot may be configured for controlled release oftherapeutic agent to tissue proximate to the implantation site of thedepot. The depots in the system may be identical or may vary in severalrespects (e.g., form factor, therapeutic agent, release profile, etc.).For example, the system may be comprised of a depot having a releaseprofile that provides for an immediate release of therapeutic agent andother depots comprised of a depot having a release profile that providesfor a delayed release of therapeutic agent.

Many depots of the present technology are configured to be implanted ata surgical site to treat postoperative pain at or near the site. As usedherein, the term “pain” includes nociception and the sensation of pain,both of which can be assessed objectively and subjectively, using painscores and other methods well-known in the art, such as opioid usage. Invarious embodiments, pain may include allodynia (e.g., increasedresponse to a normally non-noxious stimulus) or hyperalgesia (e.g.,increased response to a normally noxious or unpleasant stimulus), whichcan in turn be thermal or mechanical (tactile) in nature. In someembodiments, pain is characterized by thermal sensitivity, mechanicalsensitivity and/or resting pain. In other embodiments, pain comprisesmechanically-induced pain or resting pain. In still other embodiments,the pain comprises resting pain. The pain can be primary or secondarypain, as is well-known in the art. Exemplary types of pain reducible,preventable or treatable by the methods and compositions disclosedherein include, without limitation, include post-operative pain andneuropathic pain of the arm, neck, back, lower back, leg, and relatedpain distributions. Neuropathic pain may include pain arising fromsurgery to the nerve root, dorsal root ganglion, or peripheral nerve.

In various embodiments, the pain results from “post-surgical pain” or“post-operative pain” or “surgery-induced pain,” which are used hereininterchangeably, and refer to pain arising in the recovery period ofseconds, minutes, hours, days or weeks following a surgical procedure.Surgical procedures include any procedure that penetrates beneath theskin and causes pain and/or inflammation to the patient. Surgicalprocedure also includes arthroscopic surgery, an excision of a mass,spinal fusion, thoracic, cervical, or lumbar surgery, pelvic surgery,chest-related surgery, breast-related surgery, gynecological orobstetric surgery, general, abdominal, or urological surgery, ear, nose,and throat (ENT) surgery, oral and maxillofacial surgery, oncologicalsurgery, cosmetic surgery, or a combination thereof. FIG. 63 is a tableshowing common surgical procedures for which the depots 100 of thepresent technology may be utilized for treating postoperative pain.

Many embodiments of the present technology include one or more depots,having the same or different configuration and/or dosing, that areconfigured to be positioned at or near a surgical site to treat painassociated with recovering from a surgical procedure. As previouslydescribed, the depots of the present technology may be solid,self-supporting, flexible thin films that is structurally capable ofbeing handled by a clinician during the normal course of a surgerywithout breaking into multiple pieces and/or losing its general shape.This way, the clinician may position one or more of the depots atvarious locations at or near the treatment site, as necessary to addressa particular patient's needs and/or to target particular nervesinnervating the surgical site.

In some embodiments, the system includes a first depot (or plurality ofdepots) and a second depot (or plurality of depots), all of which areconfigured to be implanted at or near the treatment site. The firstdepot(s) may have the same or different release profile, rate ofrelease, therapeutic agent contained (such as non-anesthetic analgesics,NSAIDs, antibiotics, etc.), duration of release, size, shape,configuration, total payload, etc. as the second depot(s).

So as not to interfere or overlap with a peripheral nerve blockadministered perioperatively to the patient, one or more of the depotsmay optionally include a delay release capability for 6 to 24 hoursfollowing implantation. In some embodiments, one or more depots placedat the treatment site may be configured to have a delay in the releaseof therapeutic agent that may exceed 24 hours.

The depots disclosed herein may be used to treat postoperative painassociated with a wide variety of surgeries. For example, as summarizedin FIG. 63, the depots may be used to treat postoperative pain forchest-related surgery, breast-related surgery, gynecological orobstetric surgery, general, abdominal, or urological surgery, ear, nose,and throat (ENT) surgery, oral and maxillofacial surgery, oncologicalsurgery, or cosmetic surgery). For particular surgeries or classes ofsurgeries, one or more depots can be positioned at a treatment site totreat postoperative pain. The treatment site may be at or near thesurgical site, or in some embodiments may be separated from the surgicalsite and proximate to a target nerve or nerve bundle that innervates thesurgical site.

In one example, one or more depots as described herein can be used totreat postoperative pain associated with chest-related surgeries such asa thoracotomy, esophageal surgery, cardiac surgery, lung resection,thoracic surgery, or other such procedure. In treating postoperativepain associated with such surgeries, one or more depots can beconfigured and positioned to target the intercostal nerves, for exampleby being placed at or near the thoracic paravertebral space or othersuitable location. Analgesics delivered to the intercostal nerves canreduce pain in a patient's chest area, thereby relieving postoperativepain associated with the above-noted chest-related surgical procedures.

In another example, one or more depots disclosed herein can be used totreat postoperative pain associated with breast-related surgeries suchas a mastectomy, breast augmentation, breast reduction, breastreconstruction procedure, or other such procedure. To treatpostoperative pain from such procedures, one or more depots can bepositioned and configured to deliver analgesics or other therapeuticagents to the intercostal nerves, for example via placement at or nearthe patient's infraclavicular space or other suitable location.Additionally or alternatively, one or more depots can be positioned andconfigured to deliver analgesics or other therapeutic agents to thelateral pectoral nerve and/or the medial pectoral nerve, for example viaplacement between the serratus anterior muscle and the latissimus dorsimuscle or other suitable location. As noted above, analgesics deliveredto the intercostal nerves can reduce pain in a patient's chest area,while analgesics delivered to the lateral and/or medial pectoral nervescan reduce pain in the pectoralis major and pectoralis minor, therebyreducing postoperative pain associated with the above-notedchest-related surgical procedures.

As another example, one or more depots can be used to treatpostoperative pain associated with general, abdominal, and/or urologicalprocedures. Examples of such procedures include proctocolectomy,pancreatectomy, appendectomy, hemorrhoidectomy, cholecystectomy, kidneytransplant, nephrectomy, radical prostatectomy, nephrectomy,gastrectomy, small bowel resection, splenectomy, incisional herniarepair, inguinal hernia repair, sigmoidectomy, liver resection,enterostomy, rectum resection, kidney stone removal, and cystectomyprocedures. For such operations, postoperative pain can be treated byplacing one or more depots to target nerves at the transverse abdominisplane (TAP). Analgesics delivered to the TAP can anesthetize the nervesthat supply the anterior abdominal wall, thereby reducing postoperativepain in this region. In some embodiments, one or more depots aredisposed between the internal oblique and transverse abdominis muscles.In some embodiments, one or more depots can be disposed at or adjacentto the abdominal wall, for example being secured in place via fixationmechanisms as described in more detail below.

In some embodiments, one or more depots are used to treat postoperativepain associated with gynecological and obstetric surgeries, for examplea myomectomy, Caesarian section, hysterectomy, oophorectomy, pelvicfloor reconstruction, or other such surgical procedure. For suchprocedures, the depot(s) can be configured and positioned to deliveranalgesics or other therapeutic agents to one or more of the nervesinnervating the pelvic and/or genital area, for example the pudendalnerve, intercostal nerve, or other suitable nerve.

In some embodiments, one or more depots can be used to treatpostoperative pain associated with ear, nose, and throat (ENT) surgicalprocedures, for example tonsillectomy, submucosal resection,rhinoplasty, sinus surgery, inner ear surgery, parotidectomy,submandibular gland surgery, or other such operation. Similarly, one ormore depots can be used to treat postoperative pain associated with oraland maxillofacial surgeries, for example dentoalveolar surgery, dentalimplant surgery, orthognathic surgery, temporomandibular joint (TMJ)surgery, dental reconstruction surgeries, or other such operations. ForENT surgical procedures and oral and maxillofacial surgical procedures,the depot(s) can be configured and positioned to deliver analgesics orother therapeutic agents to one or more of the nerves innervatingregions affected by the surgical procedure, for example the mandibularnerve, the mylohyoid nerve, lingual nerve, inferior alveolar nerve,buccal nerve, auriculotemporal nerve, anterior ethmoidal nerve, or othersuitable nerve.

One or more depots 100 can also be used to treat postoperative pain forother surgical procedures, for example oncological surgeries (e.g.,tumor resection), cosmetic surgeries (e.g., liposuction), or othersurgical procedure resulting in postoperative pain. For treatment ofpostoperative pain associated with any particular surgery, the number ofdepots and the characteristics of individual depots can be selected todeliver the desired therapeutic benefits. For example, the dimensions ofthe depot(s), the amount of therapeutic agent per depot, the releaseprofile, and other characteristics can be tuned to provide the desiredtreatment of postoperative pain. For example, while a patient recoveringfrom a knee-replacement surgery may benefit from delivery of analgesicsfor at least 14 days, a patient recovering from a tonsillectomy may notrequire the same level or duration of analgesic drug delivery. As such,depots delivered to a patient for treatment of postoperative painfollowing a tonsillectomy may require fewer depots, or depots having asmaller payload of therapeutic agent, or depot(s) having a steeperrelease profile, etc. Additionally, the number and characteristics ofthe depot(s) selected for implantation can be tailored to accommodatethe target anatomical region for placement in the patient's body.

V. CONCLUSION

Although many of the embodiments are described above with respect tosystems, devices, and methods for treating postoperative pain, thetechnology is applicable to other applications and/or other approaches.For example, the depots of the present technology may be used to treatpostoperative pain associated with a veterinary procedure and/orsurgery. Moreover, other embodiments in addition to those describedherein are within the scope of the technology. Additionally, severalother embodiments of the technology can have different configurations,components, or procedures than those described herein. A person ofordinary skill in the art, therefore, will accordingly understand thatthe technology can have other embodiments with additional elements, orthe technology can have other embodiments without several of thefeatures shown and described above with reference to FIGS. 2-67.

The above detailed descriptions of embodiments of the technology are notintended to be exhaustive or to limit the technology to the precise formdisclosed above. Where the context permits, singular or plural terms mayalso include the plural or singular term, respectively. Althoughspecific embodiments of, and examples for, the technology are describedabove for illustrative purposes, various equivalent modifications arepossible within the scope of the technology, as those skilled in therelevant art will recognize. For example, while steps are presented in agiven order, alternative embodiments may perform steps in a differentorder. The various embodiments described herein may also be combined toprovide further embodiments.

Moreover, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the term “comprising” is used throughout to mean including at least therecited feature(s) such that any greater number of the same featureand/or additional types of other features are not precluded. It willalso be appreciated that specific embodiments have been described hereinfor purposes of illustration, but that various modifications may be madewithout deviating from the technology. Further, while advantagesassociated with certain embodiments of the technology have beendescribed in the context of those embodiments, other embodiments mayalso exhibit such advantages, and not all embodiments need necessarilyexhibit such advantages to fall within the scope of the technology.Accordingly, the disclosure and associated technology can encompassother embodiments not expressly shown or described herein.

Unless otherwise indicated, all numbers expressing quantities ofingredients, percentages or proportions of materials, reactionconditions, and other numerical values used in the specification andclaims, are to be understood as being modified in all instances by theterm “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the following specification andattached claims are approximations that may vary depending upon thedesired properties sought to be obtained by the present technology. Atthe very least, and not as an attempt to limit the application of thedoctrine of equivalents to the scope of the claims, each numericalparameter should at least be construed in light of the number ofreported significant digits and by applying ordinary roundingtechniques. Additionally, all ranges disclosed herein are to beunderstood to encompass any and all subranges subsumed therein. Forexample, a range of “1 to 10” includes any and all subranges between(and including) the minimum value of 1 and the maximum value of 10,i.e., any and all subranges having a minimum value of equal to orgreater than 1 and a maximum value of equal to or less than 10, e.g.,5.5 to 10.

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. For example,reference to “a therapeutic agent” includes one, two, three or moretherapeutic agents.

The headings above are not meant to limit the disclosure in any way.Embodiments under any one heading may be used in conjunction withembodiments under any other heading.

1. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising: a therapeutic regioncomprising the analgesic; a control region comprising a bioresorbablepolymer and a releasing agent mixed with the polymer, wherein thereleasing agent is configured to dissolve when the depot is placed invivo to form diffusion openings in the control region; and wherein thedepot is configured to be implanted at a treatment site in vivo and,while implanted, release the analgesic at the treatment site for no lessthan 7 days.
 2. The depot of claim 1, wherein the analgesic in thetherapeutic region comprises at least 50% of the total weight of thedepot.
 3. The depot of claim 1, wherein the depot is configured torelease the analgesic at the treatment site for no less than 14 days. 4.The depot of claim 3, wherein about 20% to about 50% of the analgesic isreleased in the first about 3 to about 5 days of the 14 days, andwherein at least 80% of the remaining analgesic is released in the last11 days of the 14 days.
 5. The depot of claim 3, wherein about 20% toabout 40% of the analgesic is released in the first 3 days of the 14days, and wherein at least 80% of the remaining analgesic is released inthe last 11 days of the 14 days.
 6. The depot of claim 3, wherein atleast 90% of the remaining analgesic is released in the last 11 days ofthe 14 days.
 7. The depot claim 3, wherein no more than 15% of theamount of analgesic is released in the first 2 days of the 14 days. 8.The depot claim 1, wherein the depot is configured to release theanalgesic at a first rate for a first period of time and at a secondrate for a second period of time.
 9. The depot of claim 8, wherein thefirst rate is greater than the second rate.
 10. The depot of claim 9,wherein the depot is configured to release at least 90% of the analgesicin the therapeutic region within 14 days.
 11. The depot of claim 1,wherein the depot is configured to release about 100 mg to about 500 mgof analgesic to the treatment site per day.
 12. A depot for thetreatment of postoperative pain via sustained, controlled release of ananalgesic, comprising: a therapeutic region comprising the analgesic; acontrol region comprising a bioresorbable polymer and a releasing agentmixed with the polymer, wherein the releasing agent is configured todissolve when the depot is placed in vivo to form diffusion openings inthe control region; wherein the depot is configured to be implanted at atreatment site in vivo and, while implanted, release the analgesic atthe treatment site for no less than 14 days, and wherein about 20% toabout 40% of the analgesic is released in the first 3 days of the 14days, and wherein at least 80% of the remaining analgesic is released inthe last 11 days of the 14 days.
 13. A depot for the treatment ofpostoperative pain via sustained, controlled release of an analgesic,comprising: a therapeutic region comprising the analgesic; a controlregion comprising a bioresorbable polymer and a releasing agent mixedwith the polymer, wherein the releasing agent is configured to dissolvewhen the depot is placed in vivo to form diffusion openings in thecontrol region; wherein the depot is configured to be implanted at atreatment site in vivo and, while implanted, release the analgesic atthe treatment site for no less than 3 days, and wherein the controlregion does not include the analgesic at least prior to implantation ofthe depot at the treatment site.
 14. A depot for the treatment ofpostoperative pain via sustained, controlled release of an analgesic,comprising: a therapeutic region comprising the analgesic; a controlregion comprising a bioresorbable polymer and a releasing agent mixedwith the polymer, wherein the releasing agent is configured to dissolvewhen the depot is placed in vivo to form diffusion openings in thecontrol region; and wherein the depot is configured to be implanted at atreatment site in vivo and, while implanted, release the analgesic atthe treatment site for no less than 3 days, wherein the control regioncomprises an analgesic different from the analgesic in the therapeuticregion.
 15. A depot for the treatment of postoperative pain viasustained, controlled release of an analgesic, comprising: a therapeuticregion comprising the analgesic; a control region comprising abioresorbable polymer and a releasing agent mixed with the polymer,wherein the releasing agent is configured to dissolve when the depot isplaced in vivo to form diffusion openings in the control region; whereinthe depot is configured to be implanted at a treatment site in vivo and,while implanted, release the analgesic at the treatment site for no lessthan 3 days, and wherein the releasing agent is a first releasing agentand the therapeutic region includes a second releasing agent mixed withthe analgesic.
 16. A depot for the treatment of postoperative pain viasustained, controlled release of an analgesic, comprising: a therapeuticregion comprising the analgesic; a control region comprising abioresorbable polymer and a releasing agent mixed with the polymer,wherein the releasing agent is configured to dissolve when the depot isplaced in vivo to form diffusion openings in the control region; whereinthe depot is configured to be implanted at a treatment site in vivo and,while implanted, release the analgesic at the treatment site for no lessthan 3 days, and wherein the releasing agent is a first releasing agentand the polymer is a first polymer, and the therapeutic region includesa second releasing agent and a second polymer mixed with the analgesic.17. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising: a therapeutic regioncomprising the analgesic; a control region comprising a bioresorbablepolymer and a releasing agent mixed with the polymer, wherein thereleasing agent is configured to dissolve when the depot is placed invivo to form diffusion openings in the control region; wherein the depotis configured to be implanted at a treatment site in vivo and, whileimplanted, release the analgesic at the treatment site for no less than3 days, and wherein a thickness of the control region is less than orequal to 1/50 of a thickness of the therapeutic region.
 18. A depot forthe treatment of postoperative pain via sustained, controlled release ofan analgesic, comprising: a therapeutic region comprising the analgesic;a control region comprising a bioresorbable polymer and a releasingagent mixed with the polymer, wherein the releasing agent is configuredto dissolve when the depot is placed in vivo to form diffusion openingsin the control region; wherein the depot is configured to be implantedat a treatment site in vivo and, while implanted, release the analgesicat the treatment site for no less than 3 days, and wherein a thicknessof the control region is less than or equal to 1/75 of a thickness ofthe therapeutic region.
 19. A depot for the treatment of postoperativepain via sustained, controlled release of an analgesic, comprising: atherapeutic region comprising the analgesic; a control region comprisinga bioresorbable polymer and a releasing agent mixed with the polymer,wherein the releasing agent is configured to dissolve when the depot isplaced in vivo to form diffusion openings in the control region; whereinthe depot is configured to be implanted at a treatment site in vivo and,while implanted, release the analgesic at the treatment site for no lessthan 3 days, and wherein a thickness of the control region is less thanor equal to 1/100 of a thickness of the therapeutic region.
 20. A depotfor the treatment of postoperative pain via sustained, controlledrelease of an analgesic, comprising: a therapeutic region comprising theanalgesic; and a control region comprising a bioresorbable polymer and areleasing agent mixed with the polymer, wherein the releasing agent isconfigured to dissolve when the depot is placed in vivo to formdiffusion openings in the control region, wherein the depot isconfigured to be implanted at a treatment site in vivo and, whileimplanted, release the analgesic at the treatment site for no less than3 days, and wherein the first control layer includes a first amount ofthe releasing agent and the second control layer includes a secondamount of the releasing agent different than the first amount.
 21. Adepot for the treatment of postoperative pain via sustained, controlledrelease of an analgesic, comprising: a therapeutic region comprising theanalgesic; a control region comprising a bioresorbable polymer and areleasing agent mixed with the polymer, wherein the releasing agent isconfigured to dissolve when the depot is placed in vivo to formdiffusion openings in the control region; wherein the depot isconfigured to be implanted at a treatment site in vivo and, whileimplanted, release the analgesic at the treatment site for no less than3 days, wherein the depot has a total surface area comprising theexposed surface area of the cover region plus the exposed surface areaof the therapeutic region, and wherein, when the depot is initiallypositioned at the treatment site in vivo, a ratio of the exposed surfacearea of the therapeutic region to the exposed surface area of the coverregion is from about 5% to about 20%, or from about 5% to about 15%, orfrom about 5% to about 10%.